EP1294414B1 - Composition and method for the repair and regeneration of cartilage and other tissues - Google Patents

Composition and method for the repair and regeneration of cartilage and other tissues Download PDF

Info

Publication number
EP1294414B1
EP1294414B1 EP01947086A EP01947086A EP1294414B1 EP 1294414 B1 EP1294414 B1 EP 1294414B1 EP 01947086 A EP01947086 A EP 01947086A EP 01947086 A EP01947086 A EP 01947086A EP 1294414 B1 EP1294414 B1 EP 1294414B1
Authority
EP
European Patent Office
Prior art keywords
blood
polymer composition
chitosan
cartilage
tissue
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP01947086A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1294414A2 (en
Inventor
Caroline D. Hoemann
Michael D. Buschmann
Marc D. Mckee
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biosyntech Canada Inc
Original Assignee
Biosyntech Canada Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biosyntech Canada Inc filed Critical Biosyntech Canada Inc
Publication of EP1294414A2 publication Critical patent/EP1294414A2/en
Application granted granted Critical
Publication of EP1294414B1 publication Critical patent/EP1294414B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/18—Erythrocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/19—Platelets; Megacaryocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3616—Blood, e.g. platelet-rich plasma
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue

Definitions

  • the invention relates to a composition to improve the repair and to regenerate cartilaginous tissues and other tissues including without limitation meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers, and its use in the manufacture of a medicament for tissue repair.
  • Cartilage Structure, Function, Development, Pathology
  • Articular cartilage covers the ends of bones in diarthroidial joints in order to distribute the forces of locomotion to underlying bone structures while simultaneously providing nearly frictionless articulating interfaces. These properties are furnished by the extracellular matrix composed of collagen types II and other minor collagen components and a high content of the proteoglycan aggrecan. In general, the fibrillar collagenous network resists tensile and shear forces while the highly charged aggrecan resists compression and interstitial fluid flow. The low friction properties are the result of a special molecular composition of the articular surface and of the synovial fluid as well as exudation of interstitial fluid during loading onto the articular surface (Ateshian, 1997; Higaki et al., 1997; Schwartz and Hills, 1998).
  • Articular cartilage is formed during the development of long bones following the condensation of prechondrocytic mesenchymal cells and induction of a phenotype switch from predominantly collagen type I to collagen type II and aggrecan (Hall, 1983; Pechak et al., 1986). Bone is formed from cartilage when chondrocytes hypertrophy and switch to type X collagen expression, accompanied by blood vessel invasion, matrix calcification, the appearance of osteoblasts and bone matrix production. In the adult, a thin layer of articular cartilage remains on the ends of bones and is sustained by chondrocytes through synthesis, assembly and turnover of extracellular matrix (Kuettner, 1992).
  • Articular cartilage disease arises when fractures occur due to physical trauma or when a more gradual erosion, as is characteristic of many forms of arthritis, exposes subchondral bone to create symptomatic joint pain (McCarty and Koopman, 1993).
  • cartilaginous tissues remain in the adult at several body sites such as the ears and nose, areas that are often subject to reconstructive surgery.
  • Articular cartilage has a limited response to injury in the adult mainly due to a lack of vascularisation and the presence of a dense proteoglycan rich extracellular matrix (Newman, 1998; Buckwalter and Mankin, 1997; Minas and Nehrer, 1997).
  • the former inhibits the appearance of inflammatory and pluripotential repair cells, while the latter emprisons resident chondrocytes in a matrix non-conducive to migration.
  • lesions that penetrate the subchondral bone create a conduit to the highly vascular bone allowing for the formation of a fibrin clot that traps cells of bone and marrow origin in the lesion leading to a granulation tissue.
  • the deeper portions of the granulation tissue reconstitute the subchondral bone plate while the upper portion transforms into a fibrocartilagenous repair tissue.
  • This tissue can temporarily possess the histological appearance of hyaline cartilage although not its mechanical properties (Wei et al., 1997) and is therefore unable to withstand the local mechanical environment leading to the appearance of degeneration before the end of the first year post-injury.
  • the natural response to repair in adult articular cartilage is that partial thickness lesions have no repair response (other than cartilage flow and localized chondrocyte cloning) while full-thickness lesions with bone penetration display a limited and failed response.
  • the bone marrow-stimulation techniques of shaving, debridement, drilling, fracturing and abrasion athroplasty permit temporary relief from symptoms but produce a sub-functional fibrocartilagenous tissue that is eventually degraded.
  • Pharmacological modulation supplying growth factors to defect sites can augment natural repair but to date insufficiently so (Hunziker and Rosenberg, 1996; Sellers et al., 1997). Allograft and autograft osteochondral tissue transplants containing viable chondrocytes can effect a more successful repair but suffer from severe donor limitations (Mahomed et al., 1992; Outerbridge et al., 1995).
  • the family of bone marrow-stimulation techniques include debridement, shaving, drilling, microfracturing and abrasion arthroplasty. They are currently used extensively in orthopaedic clinical practice for the treatment of focal lesions of articular cartilage that are full-thickness, i.e. reaching the subchondral bone, and are limited in size, typically less than 3cm 2 in area. Use of these procedures was initiated by Pridie and others (Pridie, 1959; Insall, 1967; DePalma et al., 1966) who reasoned that a blood clot could be formed in the region of an articular cartilage lesion by violating the cartilage/bone interface to induce bleeding from the bone into the cartilage defect that is avascular.
  • Abrasion arthroplasty uses motorised instruments to grind away abnormally dense subchondral bone to reach a blood supply in the softer deeper bone.
  • the microfracture technique uses a pick, or an awl, to pierce the subchondral bone plate deep enough (typically 3-4 mm), again to reach a vascular supply and create a blood clot inside the cartilage lesion.
  • Practitioners of the microfracture technique claim to observe a higher success rate than drilling due to the lack of any heat-induced necrosis and less biomechanical destabilisation of the subchondral bone plate with numerous smaller fracture holes rather than large gaps in the plate producing by drilling (Steadman et al., 1998).
  • Yet another related technique for treating focal lesions of articular cartilage is mosaicplasty or osteochondral autograft transplantation (OATS) where cartilage/bone cylinders are transferred from a peripheral "unused" region of a joint to the highly loaded region containing the cartilage lesion (Hangody et al., 1997).
  • OATS osteochondral autograft transplantation
  • Some of the problems associated with forming a good quality blood clot with these procedures are 1) the uncontrolled nature of the bleeding coming from the bone, which never fills up the cartilage lesion entirely 2) platelet mediated clot contraction occurring within minutes of clot formation reduces clot size and could detach it from surrounding cartilage (Cohen et al., 1975) 3) dilution of the bone blood with synovial fluid or circulating arthroscopy fluid and 4) the fibrinolytic or clot dissolving activity of synovial fluid (Mankin, 1974).
  • PHA polylactic acid
  • PGA polyglycolic acid
  • fibrin glues including bone morphogenetic proteins (Sellers et al., 1997; Sellers, 2000; Zhang et al. Patent WO 00/44413, 2000), angiotensin-like peptides (Rodgers and Dizerega, Patent WO 00/02905, 2000), and extracts of bone containing a multiplicity of proteins called bone proteins or BP (Atkinson, Patent WO 00/48550, 2000).
  • biomaterials compositions have also been proposed such as mixtures of collagen, chitosan and glycoaminoglycans (Collombel et al., US Patent 5,166,187, 1992; Suh et al., Patent WO 99/47186, 1999), a crushed cartilage and bone paste (Stone, US Patent 6, 110, 209, 2000), a multicomponent collagen-based construct (Pahcence et al., US Patent 6,080,194, 2000) and a curable chemically reactive methacrylate-based resin (Braden et al., US Patent 5,468,787, 1995).
  • the cell transplantation approach possesses some potential advantages over other cartilage repair techniques in that they 1) minimise additional cartilage and bone injury, 2) reduce reliance on donors by ex vivo cell production, 3) could mimic natural biological processes of cartilage development, and 4) may provide tailored cell types to execute better repair.
  • One technique using autologous chondrocytes is in the public domain and is commercially available having been used in several thousand US and Swedish patients (http://www.genzyme.com). In this technique chondrocytes are isolated from a cartilage biopsy of a non-load bearing area, proliferated during several weeks, and reintroduced into the cartilage lesion by injection under a sutured and fibrin-sealed periosteal patch harvested from the patient's tibia.
  • Cell transplantation for assisted cartilage repair necessarily involves a technique to deliver and retain viable and functional transplanted cells at the site of injury.
  • press-fitting may be used by preparing an implant that is slightly larger than the defect and forcing it therein (Aston and Bentley 1986; Wakatini et al., 1989; Freed et al., 1994; Chu et al., 1997; Frankel et al., 1997; Kawamura et al., 1998). Press-fitting necessitates the use of a tissue that is formed ex vivo and thus not optimised for the geometric, physical, and biological factors of the site in which it is implanted.
  • periosteum When the implant is not amenable to press fitting, such as with contracting collagen gels or fibrin clots, implanted, often a sutured patch of periosteum or another similar tissue is used to retain the implant material within the defect site (Grande et al., 1989; Brittberg et al., 1994; Grande et al., 1989; Brittberg et al., 1996; Breinan et al., 1997). Such a technique may benefit from an ability of the periosteum to stimulate cartilage formation (O'Driscoll et al., 1988 and 1994), but suffers again from the introduction of sutures and the complex nature of the operation involving periosteal harvesting and arthrotomy.
  • a desirable cell delivery vehicle would be a polymeric solution loaded with cells which solidifies when injected into the defect site, adheres and fills the defect, and provides a temporary biodegradable scaffold to permit proper cell differentiation and the synthesis and assembly of a dense, mechanically functional articular cartilage extracellular matrix.
  • compositions and methods and modifications thereof conserving the' same basic principles, to aid repair of other tissues including meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumours, and ulcers, are obvious to those who are skilled in the art.
  • Chitosan which primarily results from the alkaline deacetylation of chitin, a natural component of shrimp and crab shells, is a family of linear polysaccharides that contains 1-4 linked glucosamine (predominantly) and N-acetyl-glucosamine monomers (Austin et al., 1981).
  • Chitosan and its amino-substituted derivatives are pH-dependent, bioerodible and biocompatible cationic polymers that have been used in the biomedical industry for wound healing and bone induction (Denuziere et al., 1998; Muzzarelli et al., 1993 and 1994), drug and gene delivery (Carreno-Gomez and Duncan, 1997; Schipper et al., 1997; Lee et al., 1998; Bernkop-Schnurch and Pasta, 1998) and in scaffolds for cell growth and cell encapsulation (Yagi et al, 1997, Eser Elcin et al., 1998; Dillon et al., 1998; Koyano et al., 1998; Sechriest et al., 2000; Lahiji et al 2000; Suh et al., 2000).
  • Chitosan is termed a mucoadhesive polymer (Bernkop-Schnurch and Krajicek, 1998) since it adheres to the mucus layer of the gastrointestinal epithelia via ionic and hydrophobic interactions, thereby facilitating peroral drug delivery.
  • Biodegradability of chitosan occurs via its susceptibility to enzymatic cleavage by chitinases (Fukamizo and Brzezinski, 1997), lysozymes (Sashiwa et al., 1990), cellulases (Yalpani and Pantaleone, 1994), proteases (Terbojevich et al., 1996), and lipases (Muzzarelli et al., 1995).
  • chondrocytes have been shown to be capable of expressing chitotriosidase (Vasios et al., 1999), the human analogue of chitosanase; its physiological role may be in the degradation of hyaluronan, a linear polysaccharide possessing some similarity with chitosan since it is composed of disaccharides of N-acetyl-glucosamine and glucuronic acid.
  • Chitosan has been proposed in various formulations, alone and with other components, to stimulate repair of dermal, corneal and hard tissues in a number of reports (Sall et al., 1987; Bartone and Adickes, 1988; Okamoto et al., 1995; Inui et al., 1995; Shigemasa and Minami, 1996; Ueno et al., 1999; Cho et al., 1999; Stone et al., 2000; Lee et al., 2000) and inventions (Sparkes and Murray, Patent 4,572,906, 1986; Mosbey, Patent 4,956,350, 1990; Hansson et al., Patent 5,894,070, 1999; Gouda and Larm, Patent 5,902,798, 1999; Drohan et al., Patent 6,124,273, 2000; Jorgensen WO 98/22114, 1998).
  • chitosan that are most commonly cited as beneficial for the wound repair process are its biodegradability, adhesiveness, prevention of dehydration and as a barrier to bacterial invasion.
  • Other properties that have also been claimed are its cell activating and chemotractant nature (Peluso et al., 1994; Shigemasa and Minami, 1996; Inui et al., 1995) its hemostatic activity (Malette et al., 1983; Malette and Quigley, Patent 4,532,134, 1985) and an apparent ability to limit fibroplasia and scarring by promoting a looser type of granulation tissue (Bartone and Adickes, 1988; Stone et al., 2000).
  • chitosan often presents is a low solubility at physiological pH and ionic strength, thereby limiting its use in a solution state.
  • dissolution of chitosan is achieved via the protonation of amine groups in acidic aqueous solutions having a pH ranging from 3.0 to 5.6.
  • Such chitosan solutions remain soluble up to a pH near 6.2 where neutralisation of the amine groups reduces interchain electrostatic repulsion and allows attractive forces of hydrogen bonding, hydrophobic and van der Waals interactions to cause polymer precipitation at a pH near 6.3 to 6.4.
  • a prior invention (Chenite Patent WO 99/07416; Chenite et al., 2000) has taught that admixing a polyol-phosphate dibasic salt (i.e. glycerol-phosphate) to an aqueous solution of chitosan can increase the pH of the solution while avoiding precipitation.
  • a polyol-phosphate dibasic salt i.e. glycerol-phosphate
  • chitosan solutions of substantial concentration (0.5-3%) and high molecular weight (> several hundred kDa) remain liquid, at low or room temperature, for a long period of time with a pH in a physiologically acceptable neutral region between 6.8 and 7.2.
  • This aspect facilitates the mixing of chitosan with cells in a manner that maintains their viability.
  • C/PP chitosan/polyol-phosphate
  • NN-dicarboxylmethyl chitosan sponges have been soaked with BMP7 and placed into osteochondral defects of rabbits (Mattioli-Belmonte, 1999).
  • some improved histochemical and immunohistochemical outcome was observed, however, incomplete filling of the defect with repair tissue and a significant difficulty in retaining the construct within the defect appeared to be insurmountable problems.
  • the present invention overcomes these issues and presents several novel solutions for the delivery of compositions for the repair of cartilage and other tissues.
  • This macromolecular environment or matrix should 1) be amenable to loading with active biological elements (cells, proteins, genes, blood, blood components) in a liquid state 2) then be injectable into the defect site to fill the entire defect or region requiring cartilage growth 3) present a primarily nonproteinaceous environment to limit cell adhesion and cell-mediated contraction of the matrix, both of which induce a fibrocytic cellular phenotype (fibrous tissue producing) rather than chondrocytic cellular phenotype (cartilaginous tissue producing) and which can also disengage the matrix from the walls of the defect 4) be cytocompatible, possessing physiological levels of pH and osmotic pressure and an absence of any cytotoxic elements 5) be degradable but present for a sufficiently long time to allow included biologically active elements to fully reconstitute a cartilaginous tissue capable of supporting mechanical load without degradation.
  • active biological elements cells, proteins, genes, blood, blood components
  • One aim of the present invention is to provide a new composition for use in repair and regeneration of cartilaginous tissues.
  • compositions for use in repair, regeneration, reconstruction or bulking of tissues of cartilaginous tissues or other tissues such as meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers.
  • a polymer solution that can be mixed with biological elements and placed or injected into a body site where the mixture aids the repair, regeneration, reconstruction or bulking of tissues.
  • Repaired tissues include for example without limitation cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers.
  • the present invention is directed to a polymer composition for use in repairing a tissue of a patient.
  • the polymer composition is mixed with at least whole blood, said polymer composition when mixed with whole blood resulting in a mixture, said mixture turning into a non-liquid state in time or upon heating.
  • the mixture is retained at the site of introduction and adheres thereto for repairing the tissue.
  • the polymer composition comprises a polymer and is dissolved or suspended in a buffer containing an inorganic or organic salt.
  • the polymer is preferably a modified or natural polysaccharide.
  • composition of the invention may be used in a method for repairing a tissue of a patient, said method comprising the step of introducing into said tissue a temperature-dependent polymer gel composition such that said composition adhere to the tissue and promote support for cell proliferation for repairing the tissue.
  • the composition comprises whole blood.
  • a method for repairing a tissue of a patient comprising the step of introducing a polymer composition in said tissue, said polymer composition being mixable with at least one blood component, said polymer composition when mixed with said blood component results in a mixture, said mixture turning into a non-liquid state in time or upon heating, said mixture being retained at the site of introduction and adhering thereto for repairing the tissue.
  • the polymer used in the invention can be a modified or natural polysaccharide, such as chitosan, chitin, hyaluronan, glycosaminoglycan, chondroitin sulphate, keratin sulphate, dermatan sulphate, heparin, or heparin sulphate.
  • chitosan chitin
  • hyaluronan glycosaminoglycan
  • chondroitin sulphate keratin sulphate
  • dermatan sulphate dermatan sulphate
  • heparin or heparin sulphate.
  • the polymer composition may comprise a natural, recombinant or synthetic protein such as soluble collagen or soluble gelatine or a polyamino acids, such as for example a polylysine.
  • the polymer composition may comprise polylactic acid, polyglycolic acid, a synthetic homo and block copolymers containing carboxylic, amino, sulfonic, phosphonic, phosphenic functionalities with or without additional functionalities such as for example without limitation hydroxyl, thiol, alkoxy, aryloxy, acyloxy, and aroyloxy.
  • the polymer composition is preferably initially dissolved or suspended in a buffer containing inorganic salts such as sodium chloride, potassium calcium, magnesium phosphate, sulphate, and carboxylate.
  • inorganic salts such as sodium chloride, potassium calcium, magnesium phosphate, sulphate, and carboxylate.
  • the polymer composition may be dissolved or suspended in a buffer containing an organic salt such as glycerol-phosphate, fructose phosphate, glucose phosphate, L-Serine phosphate, adenosine phosphate, glucosamine, galactosamine, HEPES, PIPES, and MES.
  • an organic salt such as glycerol-phosphate, fructose phosphate, glucose phosphate, L-Serine phosphate, adenosine phosphate, glucosamine, galactosamine, HEPES, PIPES, and MES.
  • the polymer composition has preferably a pH between 6.5 and 7.8 and an osmolarity adjusted to a physiological value between 250 mOsm/L and 600 mOsm/L.
  • the blood may be for example without limitation venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood, or placenta blood. It may also comprise erythrocytes, leukocytes, monocytes, platelets, fibrinogen, thrombin or platelet rich plasma free of erythrocytes.
  • the blood can also comprise an anticoagulant such as citrate, heparin or EDTA.
  • an anticoagulant such as citrate, heparin or EDTA.
  • a pro-coagulant such as thrombin, calcium, collagen, ellagic acid, epinephrine, adenosine diphosphate, tissue factor, a phospholipid, and a coagulation factor like factor VII to improve coagulation/solidification at the site of introduction.
  • the blood may be autologous or non-autologous.
  • the polymer composition is preferably used in a ratio varying from 1:100 to 100:1 with respect to the blood.
  • the polymer composition and the whole blood are preferably mechanically mixed using sound waves, stirring, vortexing, or multiple passes in syringes.
  • the polymer composition may comprise 1.5% w/v of chitosan.
  • the tissues that can be repaired or regenerated is for example without limitation cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissue, abscesses, resected tumors, or ulcers.
  • the site of introduction in the body may be surgically prepared to remove abnormal tissues. Such procedure can be done by piercing, abrading or drilling into adjacent tissue regions or vascularised regions to create channels for the polymer composition to migrate into the site requiring repair.
  • a chitosan solution for use in cell delivery to repair or regenerate a tissue in vivo, said chitosan solution comprising 0.5-3% w/v of chitosan and being formulated to be thermogelling, said solution being mixed with cells prior to being injected into a tissue to be repaired or regenerated.
  • the solution may be induced to thermogel by addition of phosphate, glycerol phosphate or glucosamine, just to name a few for example.
  • the chitosan solution has a pH between 6.5 to 7.8.
  • the cells may be selected for example from the group consisting of primary cells, passaged cells, selected cells, platelets, stromal cells, stem cells, and genetically modified cells.
  • a carrier solution such as a solution containing hyaluronic acid, hydroxyethylcellulose, collagen, alginate, or a water-soluble polymer.
  • a gelling chitosan solution for use in culturing cells in vitro, said chitosan solution comprising 0.5-3% w/v of chitosan and being formulated to be thermogelling, said solution is mixed with cells prior to being cultured in vitro.
  • the polymer composition of this culturing medium contains between 0.01 and 10% w/v of 20% to 100% deacetylated chitosan with average molecular weight ranging from 1kDa to 10Mda and blood.
  • the invention also relates to the use of the polymer composition of the invention as described above for the manufacture of a medicament for tissue repair.
  • the tissue to be repaired is selected from the group consisting of cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumours, and ulcers and preferably said tissue is cartilage.
  • polymer or “polymer solution”, both interchangeable in the present application are intended to mean without limitation a polymer solution, a polymer suspension, a polymer particulate or powder, and a polymer micellar suspension.
  • repair when applied to cartilage and other tissues is intended to mean without limitation repair, regeneration, reconstruction, reconstitution or bulking of tissues.
  • the polymer When combined with blood the polymer could be in an aqueous solution or in an aqueous suspension, or in a particulate state, the essential characteristics of the polymer preparation being that 1) it is mixable with blood, 2) that the resulting mixture is injectable or can be placed at or in a body site that requires tissue repair, regeneration, reconstruction or bulking and 3) that the mixture has a beneficial effect on the repair, regeneration, reconstruction or bulking of tissue at the site of placement.
  • Examples 1 and 2 describe, as background of the invention, a thermogelling chitosan solution used to deliver primary chondrocytes to subcutaneous regions in mice or to culture chambers in vitro.
  • a thermogelling chitosan solution used to deliver primary chondrocytes to subcutaneous regions in mice or to culture chambers in vitro.
  • the absence of blood components necessitates a gelling capability on the part of the chitosan solution alone, and this property is endowed via a particular preparation of the chitosan solution using glycerol phosphate and other similar buffers.
  • the polymer solution may be mixed with cells and the polymer/cell solution injected in vivo or in vitro whereupon it gels, maintaining functionality and viability of the cells (Figs. 1-11).
  • the cells may be resuspended in a physiological buffer, or other cell carrier suspension such as cellulose in an isotonic buffer, prior to mixing with the chitosan solution.
  • a physiological buffer or other cell carrier suspension such as cellulose in an isotonic buffer
  • Other cell types may be used and concentrations of the chitosan and the buffer may be changed to achieve the same result.
  • Example 3 describes the use of thermogelling chitosan in vivo, without blood or cells as background of the invention.
  • thermogelling chitosan solution with primary chondrocytes for in vitro growth of cartilage
  • Chitosan (0.22g, 85% deacetylated) as an HCl salt powder was sterilised by exposure to ultraviolet radiation in a biological laminar flow hood and then dissolved in 7.5ml H 2 O resulting in a pH near 5.0.
  • D(+)-glucosamine (0.215g, MW 215.6) was dissolved in 10ml of 0.1M NaOH and filter sterilised using a 22 ⁇ m pore size disk filter.
  • Glycerol phosphate (0.8g, MW 297 including 4.5 mole water per mole glycerol phosphate) was dissolved in 2.0 ml of H 2 O and filter sterilized using a 22 ⁇ m pore size disk filter.
  • a solution is prepared by dissolving 150 mg hydroxyethyl cellulose (Fluka) and 6 ml DMEM (Dulbecco's modified Eagles Medium), and filter sterilized using a 22 ⁇ m pore size disk filter.
  • a cell pellet is resuspended with 2 ml of hydroxyethyl cellulose-DMEM solution, and admixed into the chitosan-glycerol phosphate solution.
  • the chitosan solution mixed with 2 ml of hydroxyethyl cellulose-DMEM solution with no cells was generated.
  • this solution is heated to 37°C it transforms into a solid hydrogel similarly to the thermogelling solution disclosed in a previous invention (Chenite et al. Patent WO 99/07416).
  • this previous invention did not demonstrate that cell viability was maintained throughout the thermogelling process in this chitosan solution, and thus did not enable the use of this chitosan solution for cell delivery, tissue repair and tissue regeneration.
  • Fig. 1A a cell pellet is resuspended and admixed (Fig. 1B) into the liquid chitosan gel solution at 4°C.
  • Fig. 1C and 1D the liquid solution is poured into a tissue culture petri and allowed to solidify at 37°C for 30 minutes, after which the solid gel with cells is washed with DMEM, and discs cored using a biopsy punch.
  • Fig. 1E 1000 ⁇ m pore mesh grids are placed in 48-well plates.
  • Fig. 1F the chitosan gel discs with cells are placed in culture in individual wells.
  • FIG. 2A A gel harboring cells formed after a 20 minute incubation at 37°C. Using a biopsy punch, 6 mm diameter 1 mm thick discs were cored from the gel and placed in culture for up to 3 weeks. Discs were cultured individually in 48-well tissue culture plates with sterile nylon 1000 ⁇ M meshes beneath to allow media access to all surfaces. Over 90% of the encapsulated cells were viable immediately after encapsulation, and throughout the culture period (Figs. 2A to 2C). Samples were incubated in calcein AM and ethidium homodimer-1 to reveal live (green) and dead (red) cells. Freshly isolated chondrocytes (Fig. 2A) were encapsulated in the gel, solidified and tested immediately for viability (Fig. 2B), or after 20 days of culture in the gel (Fig. 2C). Fig. 2C shows cells with typical chondrocyte morphology from the middle of the gel.
  • the chitosan gel matrix was also found to bind Toluidine blue (Fig. 3C). This property enabled to observe the lattice structure of the gel, after employing an aldehyde fixation. Interestingly, the pericellular ring of GAG observed around the chondrocytes contained little chitosan matrix, the latter appearing to have been degraded by chondrocyte-produced factors (Fig. 3D).
  • Primary calf chondrocytes were encapsulated in chitosan gel at 2x10 7 primary chondrocytes per ml and cultured as 6 mm discs for up to 20 days. Primary calf chondrocytes were encapsulated and cultured in 2% agarose and analyzed in parallel.
  • RNA analysis of type II collagen and aggrecan mRNA expressed by the encapsulated chondrocytes revealed high levels at 14 and 22 days of culture (Fig. 4, lanes 4 and 5) that were comparable to those levels observed in articular chondrocytes in cartilage (Fig. 4, lane 6).
  • a mixture of antisense 32 P-labeled RNA-probes complementary to bovine type II collagen, aggrecan, and GAPDH was hybridized with tRNA (lane 1), or total RNA, from bovine kidney (lane 2), from primary chondrocytes (10 7 /ml) cultured in chitosan gel for 0 days (lane 3) 14 days (lane 4) or 20 days (lane 5), or adult bovine articular cartilage (lane 6).
  • Discs containing primary bovine articular chondrocytes were mechanically evaluated at days 4 and 13 of culture using uniaxial unconfined compression stress relaxation tests. By comparing to control gels with no cells, a significant, cell-dependent degree of stiffening was observed even at day 4 and became much more dramatic at day 13 (Fig. 6).
  • Discs ( ⁇ 5mm diameter) from days 4, 13 and 19 of culture were mechanically tested in unconfined compression by applying 5 ramps of 10% the disk thickness ( ⁇ 1.5mm) during 10 seconds and holding that displacement during subsequent stress relaxation (the 2nd ramp from 10-20% is shown in the graph).
  • the gel discs without cells displayed a weak behavior while cell-laden gels became evidently stiffer with time in culture and more characteristically viscoelastic, like articular cartilage.
  • thermogelling chitosan solution with primary chondrocytes and subcutaneous injection for in vivo growth of cartilage
  • Athymic mice (CD1 nu/nu) were subjected to dorsal, subcutaneous injections of 100 to 300 ⁇ l of chitosan gel described in Example 1, containing 10 million calf articular chondrocytes per ml (Fig. 7).
  • a cell pellet of primary calf chondrocytes was admixed with liquid chitosan gel at 4°C to achieve a concentration of 1 to 2 x 10 7 cells/ml, and injected in liquid form as 100 ⁇ l subcutaneous dorsal implants in anesthetized nude mice.
  • In situ gelling was apparent by palpation 5 to 10 minutes post-injection.
  • mice were similarly injected with chitosan gel alone. A palpable gel was formed within 10 minutes of injection. Implants were recovered at 21, 48, and 63 days post-injection. Toluidine blue staining revealed the gross production of GAG-rich extracellular matrix by the implants containing cells (Fig. 8A). No GAG accumulation was seen in implants of chitosan gel alone (Fig. 8B). Primary calf chondrocytes at 2 x 10 7 cells/ml liquid chitosan gel were injected in liquid form as 100 ⁇ l subcutaneous dorsal implants in anesthetized nude mice. Control mice received 100 ⁇ l subcutaneous dorsal implants of liquid chitosan gel alone.
  • Cartilage-specific mRNA expression, collagen type II and aggrecan was detected in the in vivo implants with primary chondrocytes at day 48 post-injection (Fig. 9).
  • Samples were treated with RNase A and T1, then submitted to electrophoresis and autoradiography. Protected bands showing the presence of individual transcripts are as indicated.
  • the maintenance in vivo of the chondrocyte phenotype in the chitosan/glycerol-phosphate gel is shown by the expression of aggrecan and type II collagen.
  • Cartilage-specific proteins were detected in in vivo implants with primary chondrocytes from days 48 and 63 post-injection (Fig. 10). No cartilage-specific proteins were detected in implants with chitosan gel only (Fig. 10). Total proteins were extracted, separated by SDS-PAGE, and immunoblotted with antisera recognizing vimentin, PCNA, the C-propeptide of type II collagen, or cartilage link protein.
  • Samples analysed include chitosan gel with no cells (lane 1), bovine kidney (lane 2), two distinct in vivo nude mouse implants of chitosan gel only at day 63(lanes 3 and 4), of in vivo implants of chitosan gel with 2 x 10 7 calf chondrocytes per ml gel at days 48 (lane 5) or day 63 (lane 6), 2-week calf cartilage (lane 7), or adult bovine cartilage (lane 8).
  • Results show the accumulation of cartilage-specific extracellular matrix proteins CP2 and link, in only those chitosan gel implants carrying chondrocytes.
  • PCNA means "proliferating cell nuclear antigen".
  • CP refers to type 2 collagen C pro-peptide and link refers to cartilage link protein.
  • chondrocytes can be delivered in situ, via injection, with the chitosan thermogelling solution as a carrier. The injected chondrocytes remain viable, and synthesize and assemble significant levels of a proteoglycan-rich extracellular matrix that stiffens over time to form a functional cartilaginous tissue.
  • Fig. 11 The in vivo implants with no cells had a pasty consistency, whereas the implants with cells could be cored into 3 to 5 mm discs and subjected to mechanical testing to reveal a high mechanical stiffness not found in an in vitro disc without cells.
  • the equilibrium modulus at 20% and 50% compression offset is shown for the 48 day implant containing cells compared to a control disk left in vitro during a 42 day period.
  • the in vivo grown chondrocyte laden gel has developed substantial mechanical stiffness during 48 days due to the synthesis and assembly of a functional cartilage matrix (Fig. 8A).
  • thermogelling chitosan solution Adhesion of thermogelling chitosan solution to cartilage and bone surfaces
  • Fig. 12B The articulating cartilage surface was opposed and simulated joint motions were performed after which the gel was observed to remain in the cartilage defect (Fig. 12B).
  • the gel not only remained in the defect but also adhered to the surrounding bone and cartilage surfaces and did not contract.
  • Figs. 12A and 12B liquid chitosan gel was deposited in 6 mm diameter full-thickness cartilage defects (Fig. 12A) and allowed to solidify at 37°C for 30 minutes in a humidified incubator. The joint was then closed, and joint motion simulated for several minutes. The chitosan gel adhered to and was retained in all of the defects after simulated joint motion (Fig. 12B).
  • thermogelling chitosan gel revealed the retention of this thermogelling chitosan gel in the very thin cartilage layer of the rabbit (only about 0.8mm thick).
  • the gel adhered firmly to surrounding bone and cartilage tissue, demonstrating good retention, thereby enabling its use as an injectable thermogelling polymer delivery vehicle for the repair of cartilage and other tissues.
  • the joint and defect shown in Fig. 13B (filled with thermogelling chitosan, and residing 24 hours in vivo ) was fixed, embedded in LR White plastic resin, sectioned, and stained with Toluidine Blue. A cross-section of the defect reveals retention of the chitosan gel in situ, as well as adherence to cartilage and bone surfaces in the defect.
  • Fig. 15A Several distinct mixing methods were employed to admix blood with an aqueous polymer solution (Fig. 15A). Blood and polymer are admixed in a recipient, resulting in a homogenous liquid blend of blood and polymer.
  • peripheral blood from either rabbit artery, or human or equine vein was drawn into a sterile 10ml syringe.
  • a 20-gauge needle was attached to the syringe, and inserted through the rubber stopper of the vial. 6ml of peripheral blood was admitted to the vial.
  • the vial was vortex mixed for 10 seconds at full speed. Following any of these mixing techniques, the resulting mixture was deposited into a 4 ml borosilicate glass vial at room temperature, a plastic vial at 37°C, or an agarose well (Figs. 15B and 15C), or an articular cartilage defect ex vivo. As a control, the same treatment was performed with peripheral whole blood only.
  • a vacutainer vial of EDTA-treated blood was drawn to measure CBC and platelet number. All blood samples tested displayed normal CBC and platelet counts for the respective species. Regardless of the species, the prepared blood/polymer, solidified and adhered strongly to the walls of the glass vial within 2.5 to 18 minutes after mixing (Fig. 16). Mixed whole peripheral blood solidified in general more slowly compared to blood/chitosan gel (Fig. 16). Separate samples of blood, with or without liquid chitosan gel, were mixed and solidification time was measured by the number of minutes elapsed between mixing, and achieving, a solid adherent mass in the original mixing vial, or secondary recipient.
  • a clot contraction test was performed on an array of blood/polymer samples, using several controls (Figs. 17A, 17B and 17C).
  • One group of controls consisted of non-agitated whole peripheral blood, or agitated whole peripheral blood, or whole peripheral blood agitated 3 : 1 (volume : volume) with phosphate-buffered saline. These samples were compared with experimental samples containing 3 volumes whole peripheral blood agitated with 1 volume of distinct 1.5% polysaccharide solutions dissolved in PBS (alginate, hydroxyethyl cellulose, or hyaluronic acid).
  • FIG. 17A Another sample consisted of 3 volumes whole peripheral blood mixed with 1 volume chitosan-glycerol phosphate solution. At intervals up to 18 hours after solidification, the excluded serum for each condition was measured in triplicate, as an indication of degree of contraction.
  • Peripheral blood admixed with the polysaccharides alginate, hydroxyethyl cellulose, or hyaluronic acid contracted to 40%-50% of the original mass (Fig. 17A).
  • the blood/chitosan gel samples showed negligible contraction, with contraction to 90% of the original mass (Fig. 17A).
  • heparinised blood/chitosan gel samples also resisted contraction, to 85% of the original mass (Fig. 17A). From these data it was concluded that blood/chitosan gel resists contraction, and provides a more space-filling fibrin scaffolding inside the cartilage defect.
  • samples shown include blood (1), or mixed blood (2), blood/PBS (3), blood/chitosan in glycerol-phosphate (4), heparin blood/chitosan (5), blood/alginate (6), blood/hydroxyethyl cellulose (7), and blood/hyaluronic acid (8).
  • chitosan in glycerol-phosphate solution 1.5% chitosan in glycerol-phosphate solution, or three distinct 1.5% polysaccharide solutions, were admixed at a ratio of 1 volume polysaccharide solution, to 3' parts whole peripheral blood. 500 ⁇ l of each sample was deposited in a glass borosilicate tube and allowed to solidify for 60 minutes at 37°C. Different polysaccharides include hyaluronic acid-PBS (1), hydroxyethyl cellulose-PBS (2), alginate-PBS (3), and chitosan-glycerol phosphate (4). As a control, heparin blood only was analyzed (5). After 60 minutes, the tubes were laid horizontally and photodocumented. Only the mixture of chitosan-glycerol phosphate and heparinised blood became solid.
  • FIGs. 19A to 19C Histological sections of solid blood/polymer samples showed that mixtures were homogenous, that red blood cells did not hemolyse after mixing or solidification, and that platelets became activated and were functional (as evidenced by the generation of a dense fibrin network) (Figs. 19A to 19C).
  • a solidified mixture of blood/chitosan was fixed, embedded in LR White plastic, sectioned, and stained with Toluidine Blue.
  • Fig. 19A at 20x magnification, global homogeneous mixing is apparent.
  • Fig. 19B at 100x magnification, intermixed pools of red blood cells and chitosan hydropolymer is apparent.
  • 2000x magnification by environmental electron scanning microscopy
  • Fig. 20 Some leukocytes remained viable a number of hours following mixing and solidification (Fig. 20). Peripheral whole blood was mixed with chitosan gel and allowed to solidify. In Fig. 20A, 60 minutes post-solidification, the plug was placed in viability stain with calcein AM/ethidium homodimer-1 to reveal live white blood cells (green cells, large arrows), live platelets (green cells, small arrows), and dead white blood cells (red nuclei). In Fig. 20B, a distinct sample was fixed at 180 minutes post-solidification, embedded in LR-White, and submitted to Transmission Electron Microscopy. Active phagocytosis by peripheral monocytes (arrow head), reflecting cell viability, is evident in TEM micrographs at 3 hours post-mixing and solidification.
  • Serum proteins were released more slowly more sustained from the blood/chitosan samples compared with blood samples (Fig. 21). These data suggest that blood and platelet-derived proteins involved in wound healing are released in a more sustained and prolonged manner from blood/chitosan-filled defects, compared with blood clot-filled defects.
  • Solid discs of blood/chitosan gel, or blood only were generated from 150 ⁇ l initial liquid volume. Resulting discs were washed in 1 ml PBS for 3 hours, then transferred successively at 4, 5, 7, and 19 hours for a total of four additional 1 ml PBS washes. After 3 or 19 hours of washing, representative discs were extracted with GuCl to solubilise total retained proteins.
  • Soluble proteins were precipitated from equal volumes of GuCl extracts or PBS washes, separated on SDS-PAGE gels, and stained for total proteins using Sypro Orange. Comparatively, more proteins were retained in the blood/polymer discs than the blood discs throughout the 19 hour wash period. Comparatively, a slower and more prolonged release of serum proteins into the PBS washes was seen for blood/chitosan than blood over the 19 hour wash period.
  • Figs. 22A to 22C Chondral defects with perforations to the subchondral bone were treated with a peripheral blood/chitosan-glycerol phosphate mixture that was delivered as a liquid, and allowed to solidify in situ.
  • Fig. 22A a full-thickness cartilage defect, 3 x 4 mm square, was created in the femoral patellar groove of an adult (more than 7 months) New Zealand White rabbit.
  • Fig. 22B liquid whole blood was mixed at a ratio of 3 volumes blood to 1 volume chitosan in glycerol phosphate solution, and deposited to fill the defect.
  • Fig. 22C after 5 minutes in situ, the blood/chitosan implant appeared to solidify. The capsule and skin were sutured, and the animal allowed to recover with unrestricted motion.
  • FIG. 22D A similar treatment in human patients is schematized in Fig. 22D, where prepared cartilage defects receive an arthroscopic injection of liquid blood/polymer that solidifies in situ.
  • an arthroscopic injection of liquid polymer is mixed with bone-derived blood at the defect site (Fig. 22E).
  • the patient blood is mixed with the polymer ex vivo, and delivered to a prepared defect by arthroscopic injection, or (Fig.' 22E) the polymer is delivered arthroscopically or during open knee surgery and mixed at the defect site with' patient blood issuing from the defect.
  • 750 ⁇ l blood was drawn into a sterile 1cc syringe.
  • a second syringe holding 250 ⁇ l of chitosan-glycerol phosphate solution (1.5% chitosan/70 mM HCl/135 mM ⁇ -glycerol phosphate) was interconnected with the blood-containing syringe with a sterile plastic connector.
  • the syringes were pumped back-and-forth 40 times.
  • the mix was drawn into one syringe, to which a 20-gauge needle was attached. After purging half of the mix, one drop (about 25 ⁇ l) was deposited into the defect.
  • chondral defect with microdrill holes was created in both femoral patellar grooves of an adult New Zealand White rabbit, one of which was filled with blood/chitosan gel, and another left untreated.
  • the joints were fixed, processed in LR-White, and Toluidine blue stained.
  • Fig. 23A a large number of cells migrating towards the defect filled with blood/chitosan were evident
  • Fig. 23B fewer migrating cells were seen at the same region of the untreated defect
  • the blood/chitosan-treated defect was filled with hyaline repair tissue in 2 rabbits (1 male, 1 female) (Fig. 24A).
  • This blood/chitosan-based repair tissue had the appearance of hyaline, GAG-rich cartilage repair tissue.
  • the repair tissue from untreated, or blood-only treated microfracture defects, had the appearance of fibrocartilage (Fig. 24B).
  • chondral defect with microdrill holes was created in both femoral patellar grooves of an adult New Zealand White rabbit, one of which was filled with blood/chitosan gel, and another left untreated. At 51 or 56 days after healing, the joints were fixed, processed in LR-White, and Toluidine blue stained.
  • repair tissue from the blood/chitosan-treated defect had the appearance of metachromatically staining hyaline cartilage, which adhered to the defect surfaces, and filled the defect.
  • repair tissue from the untreated defect had the appearance of fibro-cartilage, with practically no metachromatic staining for GAG, and only partial defect filling.
  • Examples include: 1) altered chitosan concentration and mixing ratio with blood 2) altered choice of aqueous solution by changing buffer type and species concentration 3) an aqueous suspension of chitosan aggregates 4) a particulate chitosan powder combined with a proper mixing technique to distribute these particle throughout the blood and partly dissolve them.
  • Other polymers may be used such as 1) another polysaccharide like hyaluronan if its anti-coagulant effect is overcome by formulating it in a procoagulating state (such as by using a low concentration or combining it with thrombin) and 2) a protein polymer such as polylysine or collagen could be used to achieve similar effects.
  • these and other formulations are considered part of the present invention since they possess the characteristics of the polymer preparation of the present invention being that 1) it is mixable with blood or selected components of blood, 2) that the resulting mixture is injectable or can be placed at or in a body site that requires tissue repair, regeneration, reconstruction or bulking and 3) that the mixture has a beneficial effect on the repair, regeneration, reconstruction or bulking of tissue at the site of placement.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Dermatology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Botany (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Neurosurgery (AREA)
  • Inorganic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP01947086A 2000-06-29 2001-06-29 Composition and method for the repair and regeneration of cartilage and other tissues Expired - Lifetime EP1294414B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21471700P 2000-06-29 2000-06-29
US214717P 2000-06-29
PCT/CA2001/000959 WO2002000272A2 (en) 2000-06-29 2001-06-29 Composition and method for the repair and regeneration of cartilage and other tissues

Publications (2)

Publication Number Publication Date
EP1294414A2 EP1294414A2 (en) 2003-03-26
EP1294414B1 true EP1294414B1 (en) 2006-03-15

Family

ID=22800161

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01947086A Expired - Lifetime EP1294414B1 (en) 2000-06-29 2001-06-29 Composition and method for the repair and regeneration of cartilage and other tissues

Country Status (21)

Country Link
US (4) US20020082220A1 (zh)
EP (1) EP1294414B1 (zh)
JP (1) JP5089006B2 (zh)
KR (1) KR100880622B1 (zh)
CN (1) CN1471412B8 (zh)
AT (1) ATE320277T1 (zh)
AU (2) AU6888201A (zh)
BR (1) BR0112109A (zh)
CA (1) CA2412505C (zh)
CY (1) CY1106313T1 (zh)
DE (1) DE60117984T8 (zh)
DK (1) DK1294414T3 (zh)
ES (1) ES2260241T3 (zh)
HK (1) HK1055563A1 (zh)
IL (2) IL153490A0 (zh)
MX (1) MXPA03000203A (zh)
NZ (1) NZ523763A (zh)
PT (1) PT1294414E (zh)
SG (1) SG149679A1 (zh)
WO (1) WO2002000272A2 (zh)
ZA (1) ZA200300597B (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10179145B2 (en) 2007-03-16 2019-01-15 University Of Maryland, College Park Advanced functional biocompatible polymeric matrix used as a hemostatic agent and system for damaged tissues and cells

Families Citing this family (282)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040081704A1 (en) * 1998-02-13 2004-04-29 Centerpulse Biologics Inc. Implantable putty material
US6964685B2 (en) 1999-06-22 2005-11-15 The Brigham And Women's Hospital, Inc. Biologic replacement for fibrin clot
EP1229940B1 (en) 1999-11-15 2014-05-14 Piramal Healthcare (Canada) Limited Temperature-controlled and ph-dependant self-gelling biopolymeric aqueous solution
AU1979201A (en) * 1999-12-09 2001-06-18 Bio Syntech Canada Inc Mineral-polymer hybrid composition
US20030158302A1 (en) * 1999-12-09 2003-08-21 Cyric Chaput Mineral-polymer hybrid composition
US20020082220A1 (en) * 2000-06-29 2002-06-27 Hoemann Caroline D. Composition and method for the repair and regeneration of cartilage and other tissues
US7548865B2 (en) * 2000-10-20 2009-06-16 Arthrex, Inc. Method of selling procedure specific allografts and associated instrumentation
EP1335687B1 (en) * 2000-11-15 2007-01-10 Bio Syntech Canada Inc. Method for restoring a damaged or degenerated intervertebral disc
CA2365376C (en) 2000-12-21 2006-03-28 Ethicon, Inc. Use of reinforced foam implants with enhanced integrity for soft tissue repair and regeneration
US20020114795A1 (en) 2000-12-22 2002-08-22 Thorne Kevin J. Composition and process for bone growth and repair
US20040151705A1 (en) 2002-03-22 2004-08-05 Shuichi Mizuno Neo-cartilage constructs and a method for preparation thereof
US7288608B2 (en) 2001-10-10 2007-10-30 Regents Of The University Of Colorado Degradable thiol-ene polymers
US8293530B2 (en) * 2006-10-17 2012-10-23 Carnegie Mellon University Method and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
US20100254900A1 (en) * 2002-03-18 2010-10-07 Campbell Phil G Biocompatible polymers and Methods of use
US8529956B2 (en) 2002-03-18 2013-09-10 Carnell Therapeutics Corporation Methods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
WO2003079985A2 (en) * 2002-03-18 2003-10-02 Carnegie Mellon University Method and apparatus for preparing biomimetic scaffold
US7537780B2 (en) 2002-03-22 2009-05-26 Histogenics Corporation Method for preparing and implanting a cartilage construct to treat cartilage lesions
US7468192B2 (en) 2002-03-22 2008-12-23 Histogenics Corporation Method for repair of cartilage lesions
US7608258B2 (en) * 2002-04-13 2009-10-27 Allan Mishra Method for treatment of tendinosis using platelet rich plasma
US6811777B2 (en) 2002-04-13 2004-11-02 Allan Mishra Compositions and minimally invasive methods for treating incomplete connective tissue repair
US7832566B2 (en) 2002-05-24 2010-11-16 Biomet Biologics, Llc Method and apparatus for separating and concentrating a component from a multi-component material including macroparticles
US20030205538A1 (en) 2002-05-03 2003-11-06 Randel Dorian Methods and apparatus for isolating platelets from blood
US7992725B2 (en) 2002-05-03 2011-08-09 Biomet Biologics, Llc Buoy suspension fractionation system
US20050008629A1 (en) * 2002-05-08 2005-01-13 Interpore Orthopaedics, A Delaware Corporation Encapsulated AGF cells
US20060278588A1 (en) 2002-05-24 2006-12-14 Woodell-May Jennifer E Apparatus and method for separating and concentrating fluids containing multiple components
US7845499B2 (en) 2002-05-24 2010-12-07 Biomet Biologics, Llc Apparatus and method for separating and concentrating fluids containing multiple components
AU2003249642A1 (en) 2002-05-24 2003-12-12 Biomet Manufacturing Corp. Apparatus and method for separating and concentrating fluids containing multiple components
DE60334224D1 (de) * 2002-07-16 2010-10-28 Biosyntech Canada Inc Zusammensetzung für die herstellung zellkompatibler, injizierbarer, selbstgelierender chitosan lösungen zum einkapseln und verabreichen von lebenden zellen oderbiologisch aktiven faktoren
JP2004123576A (ja) * 2002-09-30 2004-04-22 Medgel Corp 多血小板血漿を含有する徐放性製剤
US7824701B2 (en) 2002-10-18 2010-11-02 Ethicon, Inc. Biocompatible scaffold for ligament or tendon repair
US20040078090A1 (en) 2002-10-18 2004-04-22 Francois Binette Biocompatible scaffolds with tissue fragments
BRPI0406931A (pt) * 2003-01-27 2006-01-03 Harvest Technologies Inc Método para a produção de um coagulante a partir de sangue total anticoagulado, kit para a preparação de um coagulante a partir de sangue total anticoagulado, e, fração de sangue humano
US8197837B2 (en) 2003-03-07 2012-06-12 Depuy Mitek, Inc. Method of preparation of bioabsorbable porous reinforced tissue implants and implants thereof
US20040176855A1 (en) * 2003-03-07 2004-09-09 Acell, Inc. Decellularized liver for repair of tissue and treatment of organ deficiency
US8226715B2 (en) 2003-06-30 2012-07-24 Depuy Mitek, Inc. Scaffold for connective tissue repair
US10583220B2 (en) 2003-08-11 2020-03-10 DePuy Synthes Products, Inc. Method and apparatus for resurfacing an articular surface
US7217294B2 (en) * 2003-08-20 2007-05-15 Histogenics Corp. Acellular matrix implants for treatment of articular cartilage, bone or osteochondral defects and injuries and method for use thereof
DE10348219A1 (de) * 2003-10-13 2005-05-12 Aesculap Ag & Co Kg Knorpelersatzimplantat und Verfahren zur Herstellung eines Knorpelersatzimplantats
US7316822B2 (en) 2003-11-26 2008-01-08 Ethicon, Inc. Conformable tissue repair implant capable of injection delivery
US7901461B2 (en) 2003-12-05 2011-03-08 Ethicon, Inc. Viable tissue repair implants and methods of use
US20070122906A1 (en) * 2003-12-29 2007-05-31 Allan Mishra Method of culturing cells
WO2005065269A2 (en) * 2003-12-29 2005-07-21 Am Biosolutions Compositions and method for decreasing the appearance of skin wrinkles
US7678780B2 (en) * 2003-12-29 2010-03-16 Allan Mishra Method of treating cancer using platelet releasate
US11395865B2 (en) 2004-02-09 2022-07-26 DePuy Synthes Products, Inc. Scaffolds with viable tissue
EP1576957A1 (en) * 2004-03-18 2005-09-21 Universiteit Twente Tissue repair using pluripotent cells
US20070190101A1 (en) * 2004-03-31 2007-08-16 Chunlin Yang Flowable bone grafts
US8137686B2 (en) 2004-04-20 2012-03-20 Depuy Mitek, Inc. Nonwoven tissue scaffold
US8221780B2 (en) 2004-04-20 2012-07-17 Depuy Mitek, Inc. Nonwoven tissue scaffold
BRPI0515191A (pt) * 2004-08-13 2008-07-08 Angiotech Internac Ag composição farmacêutica, método para aumentar osso ou substituir perda óssea, método para reduzir a dor associada com cicatriz pós-cirúrgica, método para prevenir aderência cirúrgicas, método para aumento ou reparo de pele ou tecido, método para manter volume em fluido ocular durante cirurgia ocular, método para reduzir a dor associada com osteoartrite, método para tratar doença de refluxo gastroesofágico, método para tratar ou prevenir incontinência urinária, método para tratar ou prevenir incontinência fecal, implante método e dispositivo médico
US7462268B2 (en) 2004-08-20 2008-12-09 Allan Mishra Particle/cell separation device and compositions
US20060085003A1 (en) * 2004-10-05 2006-04-20 Arthrex, Inc. Use of autogenous growth factors in bone tunnels during ligament reconstruction
US20090319045A1 (en) * 2004-10-12 2009-12-24 Truncale Katherine G Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles
US7837740B2 (en) 2007-01-24 2010-11-23 Musculoskeletal Transplant Foundation Two piece cancellous construct for cartilage repair
US7473678B2 (en) 2004-10-14 2009-01-06 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods of use thereof
US20060111778A1 (en) * 2004-10-29 2006-05-25 Michalow Alexander E Methods of promoting healing of cartilage defects and method of causing stem cells to differentiate by the articular chondrocyte pathway
US7658751B2 (en) 2006-09-29 2010-02-09 Biomet Sports Medicine, Llc Method for implanting soft tissue
US8298262B2 (en) 2006-02-03 2012-10-30 Biomet Sports Medicine, Llc Method for tissue fixation
US9017381B2 (en) 2007-04-10 2015-04-28 Biomet Sports Medicine, Llc Adjustable knotless loops
US7905904B2 (en) 2006-02-03 2011-03-15 Biomet Sports Medicine, Llc Soft tissue repair device and associated methods
US7749250B2 (en) 2006-02-03 2010-07-06 Biomet Sports Medicine, Llc Soft tissue repair assembly and associated method
US8088130B2 (en) 2006-02-03 2012-01-03 Biomet Sports Medicine, Llc Method and apparatus for coupling soft tissue to a bone
US8118836B2 (en) 2004-11-05 2012-02-21 Biomet Sports Medicine, Llc Method and apparatus for coupling soft tissue to a bone
US8137382B2 (en) 2004-11-05 2012-03-20 Biomet Sports Medicine, Llc Method and apparatus for coupling anatomical features
US7909851B2 (en) 2006-02-03 2011-03-22 Biomet Sports Medicine, Llc Soft tissue repair device and associated methods
US8361113B2 (en) 2006-02-03 2013-01-29 Biomet Sports Medicine, Llc Method and apparatus for coupling soft tissue to a bone
US8303604B2 (en) 2004-11-05 2012-11-06 Biomet Sports Medicine, Llc Soft tissue repair device and method
US9801708B2 (en) 2004-11-05 2017-10-31 Biomet Sports Medicine, Llc Method and apparatus for coupling soft tissue to a bone
US8128658B2 (en) 2004-11-05 2012-03-06 Biomet Sports Medicine, Llc Method and apparatus for coupling soft tissue to bone
IS7572A (is) * 2004-11-29 2006-05-30 Genis Ehf Aðferð og efni til lækninga
ITRM20040638A1 (it) 2004-12-24 2005-03-24 Advance Holdings Ltd Gel piastrinico semisintetico e metodo per la sua preparazione.
US7825083B2 (en) * 2005-02-10 2010-11-02 Spine Wave, Inc. Synovial fluid barrier
JP4545015B2 (ja) * 2005-02-24 2010-09-15 国立大学法人 東京医科歯科大学 骨移植片製造装置
JP2008531553A (ja) * 2005-02-25 2008-08-14 メディジーンズ カンパニー リミテッド 血漿または血清を含むアベリノ角膜ジストロフィー治療用の医薬組成物
US20060253068A1 (en) * 2005-04-20 2006-11-09 Van Bilsen Paul Use of biocompatible in-situ matrices for delivery of therapeutic cells to the heart
DE102005030614B4 (de) 2005-06-30 2014-05-08 Biotissue Ag Zellfreies Transplantat, dessen Verwendung, Verfahren zu dessen Herstellung, dabei hergestellte Matrix mit Gel und Verfahren zur Herstellung dieser Matrix mit Gel
KR100774089B1 (ko) * 2005-07-20 2007-11-06 세원셀론텍(주) 주입형 연골세포치료제의 이식방법
CA2623106C (en) 2005-09-19 2013-12-24 Histogenics Corporation Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof
US20090075383A1 (en) * 2005-11-04 2009-03-19 Bio Syntech Canada Inc. Composition and method for efficient delivery of nucleic acids to cells using chitosan
EP1945712A4 (en) * 2005-11-04 2013-05-01 Piramal Healthcare Canada Ltd BINDING OF AQUEOUS POLYELECTROLYTE SOLUTIONS BY THERMALLY INDUCED CHANGES IN THE IONIZATION CONDITION
EP1951327A2 (en) 2005-11-17 2008-08-06 Biomimetic Therapeutics, Inc. Maxillofacial bone augmentation using rhpdgf-bb and a biocompatible matrix
EP1981435A2 (en) 2006-01-25 2008-10-22 Children's Medical Center Corporation Methods and procedures for ligament repair
US8562645B2 (en) 2006-09-29 2013-10-22 Biomet Sports Medicine, Llc Method and apparatus for forming a self-locking adjustable loop
US10517587B2 (en) 2006-02-03 2019-12-31 Biomet Sports Medicine, Llc Method and apparatus for forming a self-locking adjustable loop
US8562647B2 (en) 2006-09-29 2013-10-22 Biomet Sports Medicine, Llc Method and apparatus for securing soft tissue to bone
US8652171B2 (en) 2006-02-03 2014-02-18 Biomet Sports Medicine, Llc Method and apparatus for soft tissue fixation
US9468433B2 (en) 2006-02-03 2016-10-18 Biomet Sports Medicine, Llc Method and apparatus for forming a self-locking adjustable loop
US9078644B2 (en) 2006-09-29 2015-07-14 Biomet Sports Medicine, Llc Fracture fixation device
US8801783B2 (en) 2006-09-29 2014-08-12 Biomet Sports Medicine, Llc Prosthetic ligament system for knee joint
US8968364B2 (en) 2006-02-03 2015-03-03 Biomet Sports Medicine, Llc Method and apparatus for fixation of an ACL graft
US9149267B2 (en) 2006-02-03 2015-10-06 Biomet Sports Medicine, Llc Method and apparatus for coupling soft tissue to a bone
US11259792B2 (en) 2006-02-03 2022-03-01 Biomet Sports Medicine, Llc Method and apparatus for coupling anatomical features
US8597327B2 (en) 2006-02-03 2013-12-03 Biomet Manufacturing, Llc Method and apparatus for sternal closure
US11311287B2 (en) 2006-02-03 2022-04-26 Biomet Sports Medicine, Llc Method for tissue fixation
US9538998B2 (en) 2006-02-03 2017-01-10 Biomet Sports Medicine, Llc Method and apparatus for fracture fixation
EP2311505B1 (en) * 2006-02-09 2013-11-06 BioMimetic Therapeutics, LLC Compositions and methods for treating bone
US8865869B2 (en) * 2006-03-20 2014-10-21 Worcester Polytechnic Institute Collagen and fibrin microthreads in a discrete thread model of in vitro ACL scaffold regeneration
JP5263826B2 (ja) * 2006-04-19 2013-08-14 国立大学法人名古屋大学 歯周軟組織再生用組成物及びその製造方法
US20070258941A1 (en) * 2006-05-02 2007-11-08 Pfister Brian E Methods and compositions for remediation of disc herniation by modifying structure
ITPD20060203A1 (it) * 2006-05-22 2007-11-23 Univ Degli Studi Trieste Idrogeli di miscele di polisaccaridi per l'ingegneria tissutale e la veicolazione di composti attivi
US8567609B2 (en) 2006-05-25 2013-10-29 Biomet Biologics, Llc Apparatus and method for separating and concentrating fluids containing multiple components
CN100428964C (zh) * 2006-06-29 2008-10-29 武汉理工大学 RGD多肽接枝聚(羟基乙酸-L-赖氨酸-L-乳酸)/β-磷酸三钙复合材料及其制备方法
AU2007269712B2 (en) 2006-06-30 2013-02-07 Biomimetic Therapeutics, Llc PDGF-biomatrix compositions and methods for treating rotator cuff injuries
US9161967B2 (en) 2006-06-30 2015-10-20 Biomimetic Therapeutics, Llc Compositions and methods for treating the vertebral column
WO2008011193A2 (en) * 2006-07-21 2008-01-24 Genera Doo Bmp-1 procollagen c-proteinase for diagnosis and treatment of bone and soft tissue defects and disorders
KR100825995B1 (ko) * 2006-08-03 2008-04-29 연세대학교 산학협력단 나노크기의 중합체와 자가혈액젤을 포함하는 골이식물질 및그 제조방법
WO2008024409A1 (en) * 2006-08-22 2008-02-28 The Trustees Of Columbia University In The City Of New York Progenitor cell replication and differentiation in 3d
CA2664866C (en) 2006-09-28 2018-08-14 Children's Medical Center Coporation Methods and collagen products for tissue repair
US8672969B2 (en) 2006-09-29 2014-03-18 Biomet Sports Medicine, Llc Fracture fixation device
US11259794B2 (en) 2006-09-29 2022-03-01 Biomet Sports Medicine, Llc Method for implanting soft tissue
DE102006047346A1 (de) 2006-10-06 2008-04-10 Transtissue Technologies Gmbh Matrix-Gel-Transplantat ohne Zellen
US20090169628A1 (en) * 2006-10-17 2009-07-02 Armark Authentication Technologies, Llc Article and method for focused delivery of therapeutic and/or diagnostic materials
US8529961B2 (en) 2006-10-17 2013-09-10 Carmell Therapeutics Corporation Methods and apparatus for manufacturing plasma based plastics and bioplastics produced therefrom
JP5552315B2 (ja) 2006-11-03 2014-07-16 バイオミメティック セラピューティクス， エルエルシー アースロデティック術のための組成物および方法
GB0622846D0 (en) * 2006-11-16 2006-12-27 Univ Leeds Preparation of tissue for meniscal implantation
CA2672936A1 (en) * 2006-11-30 2008-06-05 Bio Syntech Canada Inc. Method for in situ solidification of blood-polymer compositions for regenerative medicine and cartilage repair applications
US7718616B2 (en) 2006-12-21 2010-05-18 Zimmer Orthobiologics, Inc. Bone growth particles and osteoinductive composition thereof
US20080193424A1 (en) * 2007-02-09 2008-08-14 Biomet Biologics, Inc. Treatment of tissue defects with a therapeutic composition
DK2121048T3 (en) 2007-02-19 2015-11-23 Marinepolymer Tech Inc Hemostatic compositions and therapeutic regimens
US20110129544A1 (en) * 2007-02-22 2011-06-02 Tatsuya Miyazaki Bone/Cartilage Formation-Stimulation Agent
US9814581B2 (en) 2007-02-26 2017-11-14 Marvin Schwartz Mobile prosthesis for interpositional location between bone joint articular surfaces and method of use
US7670381B2 (en) * 2007-02-26 2010-03-02 Marvin Schwartz Prosthesis for interpositional location between bone joint articular surfaces and method of use
US8506637B2 (en) 2007-02-26 2013-08-13 Marvin Schwartz Mobile prosthesis for interpositional location between bone joint articular surfaces and method of use
US8034014B2 (en) 2007-03-06 2011-10-11 Biomet Biologics, Llc Angiogenesis initation and growth
US20100034898A1 (en) * 2007-03-12 2010-02-11 Thomas Joseph Lally Cartilage simulating bio-material composition and method
US20100092573A1 (en) * 2007-03-12 2010-04-15 Thomas Lally Hemostatic bio-material composition and method
US8328024B2 (en) 2007-04-12 2012-12-11 Hanuman, Llc Buoy suspension fractionation system
WO2008127639A1 (en) 2007-04-12 2008-10-23 Biomet Biologics, Llc Buoy suspension fractionation system
US8137354B2 (en) * 2007-04-25 2012-03-20 Biomet Sports Medicine, Llc Localized cartilage defect therapy
US20080269762A1 (en) * 2007-04-25 2008-10-30 Biomet Manufacturing Corp. Method and device for repair of cartilage defects
US20080268064A1 (en) * 2007-04-25 2008-10-30 Biomet Biologics, Inc. Method for treating cartilage defects
US7901344B2 (en) * 2007-05-11 2011-03-08 Biomet Biologics, Llc Methods of reducing surgical complications in cancer patients
US8133553B2 (en) 2007-06-18 2012-03-13 Zimmer, Inc. Process for forming a ceramic layer
US8309521B2 (en) 2007-06-19 2012-11-13 Zimmer, Inc. Spacer with a coating thereon for use with an implant device
US20090054984A1 (en) 2007-08-20 2009-02-26 Histogenics Corporation Method For Use Of A Double-Structured Tissue Implant For Treatment Of Tissue Defects
US8685107B2 (en) 2007-07-03 2014-04-01 Histogenics Corporation Double-structured tissue implant and a method for preparation and use thereof
US7947081B2 (en) * 2007-07-11 2011-05-24 Linares Medical Devices, Llc Skeletal implant for replacing a human bone
ES2333498B1 (es) * 2007-08-02 2011-01-10 Biotechnology Institute, I Mas D, S.L. Metodo y compuesto para el tratamiento de enfermedades o dolencias articulares o para el tratamiento de la piel con fines esteticos u otros, y el metodo de preparacion del compuesto.
WO2009026392A1 (en) 2007-08-20 2009-02-26 Histogenics Corporation A method for improvement of differentiation of mesenchymal stem cells using a double-structured tissue implant
EP2209443A4 (en) * 2007-09-17 2012-08-29 Linares Medical Devices Llc ARTIFICIAL JOINT SUPPORT BETWEEN A FIRST AND A SECOND BONE
US8697044B2 (en) 2007-10-09 2014-04-15 Allergan, Inc. Crossed-linked hyaluronic acid and collagen and uses thereof
US20110230973A1 (en) * 2007-10-10 2011-09-22 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
US8608049B2 (en) 2007-10-10 2013-12-17 Zimmer, Inc. Method for bonding a tantalum structure to a cobalt-alloy substrate
WO2009051701A2 (en) * 2007-10-15 2009-04-23 Wake Forest University Health Sciences Methods and compositions for printing biologically compatible nanotube composites of autologous tissue
US8764837B2 (en) * 2008-03-26 2014-07-01 Linares Medical Devices, Llc Reinforced joint assembly
US8979938B2 (en) * 2007-11-08 2015-03-17 Linares Medical Devices, Llc Artificial knee implant including liquid ballast supporting / rotating surfaces and incorporating flexible multi-material and natural lubricant retaining matrix applied to a joint surface
US8828088B2 (en) * 2007-11-08 2014-09-09 Linares Medical Devices, Llc Joint assembly incorporating undercut surface design to entrap accumulating wear debris from plastic joint assembly
US9539097B2 (en) 2007-11-08 2017-01-10 Linares Medical Devices, Llc Hip and knee joint assemblies incorporating debris collection architecture between the ball and seat interface
US8197507B2 (en) * 2008-01-14 2012-06-12 Sri International Sutureless methods for laceration closure
US20090187256A1 (en) * 2008-01-21 2009-07-23 Zimmer, Inc. Method for forming an integral porous region in a cast implant
US20090192528A1 (en) * 2008-01-29 2009-07-30 Biomet Biologics, Inc. Method and device for hernia repair
US20090198286A1 (en) * 2008-02-05 2009-08-06 Zimmer, Inc. Bone fracture fixation system
CN102014977B (zh) 2008-02-07 2015-09-02 生物模拟治疗有限责任公司 用于牵引成骨术的组合物和方法
DE102008008540A1 (de) * 2008-02-07 2009-08-13 Beiersdorf Ag Hautpflegezubereitung zur Pflege von gestresster Haut
US8702801B2 (en) * 2008-02-25 2014-04-22 Linares Medical Devices, Llc Artificial wear resistant plug for mounting to existing joint bone
EP2620139B1 (en) 2008-02-27 2016-07-20 Biomet Biologics, LLC Interleukin-1 receptor antagonist rich solutions
EP2254991B1 (en) 2008-02-29 2018-08-22 Biomet Manufacturing, LLC A system and process for separating a material
EP3545979A1 (en) * 2008-07-02 2019-10-02 Allergan, Inc. Compositionsand methods for tissue filling and regeneration
US9289302B2 (en) * 2008-07-28 2016-03-22 Zimmer, Inc. Mosaicplasty constructs
EP3184552B1 (en) 2008-09-02 2020-08-12 Tautona Group LP Threads of hyaluronic acid, methods of making thereof and uses thereof
NZ591338A (en) 2008-09-09 2013-02-22 Biomimetic Therapeutics Inc Platelet-derived growth factor compositions and methods for the treatment of tendon and ligament injuries
WO2010037021A2 (en) * 2008-09-29 2010-04-01 Armark Authentication Technologies, Llc Spinneret and method of spinning fiber
US20100112081A1 (en) 2008-10-07 2010-05-06 Bioparadox, Llc Use of platelet rich plasma composition in the treatment of cardiac conduction abnormalities
GB0820492D0 (en) 2008-11-07 2008-12-17 Sportcell Cell compositions and uses thereof
US9192695B2 (en) 2008-11-20 2015-11-24 Allosource Allografts combined with tissue derived stem cells for bone healing
US9308070B2 (en) 2008-12-15 2016-04-12 Allergan, Inc. Pliable silk medical device
US20100291214A1 (en) * 2008-12-23 2010-11-18 Armark Authentication Technologies, Llc Three-dimensional microfiber extrudate structure and process for forming three-dimensional microfiber extrudate structure
CA2754501A1 (en) * 2009-03-05 2010-09-10 Biomimetic Therapeutics, Inc. Platelet-derived growth factor compositions and methods for the treatment of osteochondral defects
US8187475B2 (en) 2009-03-06 2012-05-29 Biomet Biologics, Llc Method and apparatus for producing autologous thrombin
US20100233282A1 (en) * 2009-03-13 2010-09-16 Allan Mishra Device and methods for delivery of bioactive materials to the right side of the heart
US20110171180A1 (en) * 2009-03-19 2011-07-14 Worcester Polytechnic Institute Bioengineered skin substitutes
US20100249924A1 (en) * 2009-03-27 2010-09-30 Allergan, Inc. Bioerodible matrix for tissue involvement
US8313954B2 (en) 2009-04-03 2012-11-20 Biomet Biologics, Llc All-in-one means of separating blood components
WO2010123945A2 (en) 2009-04-20 2010-10-28 Allergan, Inc. Silk fibroin hydrogels and uses thereof
EP2429598A2 (en) * 2009-05-13 2012-03-21 Kitozyme S.A. Adhesive composition
US20100291384A1 (en) * 2009-05-15 2010-11-18 Armark Authentication Technologies, Llc Fiber having non-uniform composition and method for making same
US9011800B2 (en) 2009-07-16 2015-04-21 Biomet Biologics, Llc Method and apparatus for separating biological materials
WO2011011808A1 (en) * 2009-07-30 2011-02-03 Roman Buga A cosmetic composition comprising sodium chloride in combination with one or more of protein, collagen, gelatin or amino acid
US8377432B2 (en) * 2009-09-02 2013-02-19 Khay-Yong Saw Method and composition for neochondrogenesis
WO2011031642A2 (en) * 2009-09-08 2011-03-17 Musculoskeletal Transplant Foundation Inc. Tissue engineered meniscus repair composition
US20110059178A1 (en) * 2009-09-08 2011-03-10 Musculoskeletal Transplant Foundation Inc. Tissue Engineered Meniscus Repair Composition
KR101114712B1 (ko) * 2009-10-23 2012-02-29 세원셀론텍(주) 염화칼슘용액과 제1형 콜라겐으로 혈소판풍부혈장(ｐｒｐ)을 활성화하여 조직재생을 유도하는 조성물의 제조방법
EP2498820B1 (en) 2009-11-13 2019-01-09 University of Maryland, College Park Advanced functional biocompatible foam used as a hemostatic agent for compressible and non-compressible acute wounds
ES2688977T3 (es) * 2009-11-19 2018-11-07 Ortho Regenerative Technologies Inc. Formulación novedosa de mezclas de soluciones fisiológicas de quitosano-sal inorgánica/sangre para la reparación de tejidos
WO2011060545A1 (en) * 2009-11-19 2011-05-26 Corporation De L'ecole Polytechnique De Montreal Specific blood:chitosan mixing ratios producing a viscous paste-like implant with good handling properties for tissue repair
WO2011060554A1 (en) * 2009-11-19 2011-05-26 Corporation De L'ecole Polytechnique De Montreal Presolidified composition and method for in situ delivery of broad molecular weight range of chitosan implants with or without therapeutics for regenerative medicine and cartilage repair applications
WO2011060553A1 (en) * 2009-11-19 2011-05-26 Corporation De L'ecole Polytechnique De Montreal Formulation and method for rapid preparation of isotonic and cytocompatible chitosan solutions without inducing chitosan precipitation
EP2512516B1 (en) * 2009-12-18 2016-02-17 The Governing Council Of The University Of Toronto Injectable polymer composition for use as a cell delivery vehicle
US20110172180A1 (en) 2010-01-13 2011-07-14 Allergan Industrie. Sas Heat stable hyaluronic acid compositions for dermatological use
CN107080834A (zh) 2010-02-22 2017-08-22 生物模拟治疗有限责任公司 用于治疗腱病的血小板衍生生长因子组合物和方法
EP2361640A1 (en) * 2010-02-25 2011-08-31 Université de Liège Cell cultivation in chitosan alginate hydrogel beads
HUE043344T2 (hu) 2010-03-22 2019-08-28 Allergan Inc Térhálósított hidrogélek lágy szövet növelésére
US8591391B2 (en) 2010-04-12 2013-11-26 Biomet Biologics, Llc Method and apparatus for separating a material
US8926705B2 (en) 2010-05-10 2015-01-06 Linares Medical Devices, Llc Implantable joint assembly featuring debris entrapment chamber subassemblies along with opposing magnetic fields generated between articulating implant components in order to minimize frictional force and associated wear
US9352003B1 (en) 2010-05-14 2016-05-31 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US8883210B1 (en) 2010-05-14 2014-11-11 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US10130736B1 (en) 2010-05-14 2018-11-20 Musculoskeletal Transplant Foundation Tissue-derived tissuegenic implants, and methods of fabricating and using same
US8900571B2 (en) 2010-08-19 2014-12-02 Allergan, Inc. Compositions and soft tissue replacement methods
US8697057B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
US8883139B2 (en) 2010-08-19 2014-11-11 Allergan Inc. Compositions and soft tissue replacement methods
US9005605B2 (en) 2010-08-19 2015-04-14 Allergan, Inc. Compositions and soft tissue replacement methods
US8894992B2 (en) 2010-08-19 2014-11-25 Allergan, Inc. Compositions and soft tissue replacement methods
US8889123B2 (en) 2010-08-19 2014-11-18 Allergan, Inc. Compositions and soft tissue replacement methods
US8697056B2 (en) 2010-08-19 2014-04-15 Allergan, Inc. Compositions and soft tissue replacement methods
US8926963B2 (en) 2010-08-19 2015-01-06 Allergan, Inc. Compositions and soft tissue replacement methods
US8741281B2 (en) 2010-08-19 2014-06-03 Allergan, Inc. Compositions and soft tissue replacement methods
AU2011293055B2 (en) * 2010-08-27 2016-01-07 Oligo Medic Inc. Highly biocompatible dual thermogelling chitosan/glucosamine salt compositions
US8506972B2 (en) 2010-08-27 2013-08-13 Oligo Medic Inc Highly biocompatible dual thermogelling chitosan/glucosamine salt compositions
MX2013002488A (es) 2010-09-03 2013-06-03 Biomet Biologics Llc Métodos y composiciones para suministrar un antagonista del receptor interleucina-1.
WO2012068135A1 (en) 2010-11-15 2012-05-24 Zimmer Orthobiologics, Inc. Bone void fillers
WO2012103445A2 (en) 2011-01-28 2012-08-02 The Regents Of The University Of Colorado, A Body Corporate Convalently cross linked hydrogels and methods of making and using same
US20120231542A1 (en) * 2011-03-11 2012-09-13 General Biotechnology, Llc Biologically Active Human Umbilical Cord Blood Cell Extract Compounds and Methods
US20130096081A1 (en) 2011-06-03 2013-04-18 Allergan, Inc. Dermal filler compositions
US9408797B2 (en) 2011-06-03 2016-08-09 Allergan, Inc. Dermal filler compositions for fine line treatment
US9393263B2 (en) 2011-06-03 2016-07-19 Allergan, Inc. Dermal filler compositions including antioxidants
RU2740454C2 (ru) 2011-06-03 2021-01-14 Аллерган Эндюстри, Сас Составы кожного наполнителя, включая антиоксиданты
US20130244943A1 (en) 2011-09-06 2013-09-19 Allergan, Inc. Hyaluronic acid-collagen matrices for dermal filling and volumizing applications
US9662422B2 (en) 2011-09-06 2017-05-30 Allergan, Inc. Crosslinked hyaluronic acid-collagen gels for improving tissue graft viability and soft tissue augmentation
US9357991B2 (en) 2011-11-03 2016-06-07 Biomet Sports Medicine, Llc Method and apparatus for stitching tendons
US9381013B2 (en) 2011-11-10 2016-07-05 Biomet Sports Medicine, Llc Method for coupling soft tissue to a bone
US9314241B2 (en) 2011-11-10 2016-04-19 Biomet Sports Medicine, Llc Apparatus for coupling soft tissue to a bone
EP2591812A1 (en) * 2011-11-14 2013-05-15 University of Twente, Institute for Biomedical Technology and Technical Medicine (MIRA) A dextran-based tissuelette containing platelet-rich plasma lysate for cartilage repair
US9988433B2 (en) 2013-03-14 2018-06-05 Mosaic Biosciences, Inc. Covalent modification of biological macromolecules
AU2013214827A1 (en) * 2012-02-01 2014-08-21 Children's Medical Center Corporation Biomaterial for articular cartilage maintenance and treatment of arthritis
EP2822533B1 (en) 2012-02-02 2021-01-20 Mosaic Biosciences, Inc. Biomaterials for delivery of blood extracts and methods of using same
CN103316330B (zh) * 2012-06-28 2016-03-09 西藏贝珠雅药业有限公司 一种软组织创伤护理材料的组方与用途
US9642956B2 (en) 2012-08-27 2017-05-09 Biomet Biologics, Llc Apparatus and method for separating and concentrating fluids containing multiple components
CN112999245A (zh) * 2012-09-26 2021-06-22 骨治疗公司 包含溶剂/去污剂处理过的血浆(s/d血浆)的制剂及其用途
US10016527B2 (en) 2012-10-23 2018-07-10 Orthovita, Inc. Materials and methods for repair of cartilage defects
WO2014074804A2 (en) 2012-11-08 2014-05-15 Smith & Nephew, Inc. Methods and compositions suitable for improved reattachment of detached cartilage to subchondral bone
US10058352B2 (en) 2012-11-08 2018-08-28 Smith & Nephew, Inc. Methods and devices suitable for improved reattachment of detached cartilage to subchondral bone
WO2014121067A1 (en) 2013-02-01 2014-08-07 Children's Medical Center Corporation Collagen scaffolds
GB201304514D0 (en) * 2013-03-13 2013-04-24 Univ Birmingham Cell delivery
CA2914610C (en) 2013-03-13 2022-08-02 University Of Maryland Advanced functional biocompatible polymer putty used as a hemostatic agent for treating damaged tissue and cells
US10016459B1 (en) 2013-03-13 2018-07-10 BioDlogics, LLC Platelet-rich plasma derived from human umbilical cord blood
US9918827B2 (en) 2013-03-14 2018-03-20 Biomet Sports Medicine, Llc Scaffold for spring ligament repair
WO2014150784A1 (en) 2013-03-15 2014-09-25 Allosource Cell repopulated collagen matrix for soft tissue repair and regeneration
US10208095B2 (en) 2013-03-15 2019-02-19 Biomet Manufacturing, Llc Methods for making cytokine compositions from tissues using non-centrifugal methods
US9895418B2 (en) 2013-03-15 2018-02-20 Biomet Biologics, Llc Treatment of peripheral vascular disease using protein solutions
US20140271589A1 (en) 2013-03-15 2014-09-18 Biomet Biologics, Llc Treatment of collagen defects using protein solutions
US10143725B2 (en) 2013-03-15 2018-12-04 Biomet Biologics, Llc Treatment of pain using protein solutions
US9950035B2 (en) 2013-03-15 2018-04-24 Biomet Biologics, Llc Methods and non-immunogenic compositions for treating inflammatory disorders
US20140356893A1 (en) 2013-06-04 2014-12-04 Allan Mishra Compositions and methods for using platelet-rich plasma for drug discovery, cell nuclear reprogramming, proliferation or differentiation
JP6775751B2 (ja) 2013-09-30 2020-10-28 エボルブド バイ ネイチャー， インコーポレイテッド 絹タンパク質断片組成物及びそれから製造された物品
US9872705B2 (en) 2013-10-07 2018-01-23 Regentis Biomaterials Ltd. Treatment of cavities in a human body
CN106232023B (zh) 2013-10-07 2019-04-30 里捐提司生物材料有限公司 用于治疗人体内空腔的装置
US9192692B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan stenting paste
US9192574B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan paste wound dressing
ES2904359T3 (es) * 2014-02-20 2022-04-04 Ortho Regenerative Tech Inc Composiciones poliméricas liofilizadas para mezclar con plasma rico en plaquetas para formar implantes para la reparación de tejidos y/o composiciones para inyecciones terapéuticas intraarticulares
US11083758B2 (en) * 2014-05-14 2021-08-10 Prime Merger Sub, Llc Placental membrane preparations and methods of making and using same for regenerating cartilage and spinal intervertebral discs
US20170157296A1 (en) * 2014-07-21 2017-06-08 The Board Of Trustees Of The Leland Stanford Junior University Macrophage or monocyte enhanced wound healing
EP3174498A4 (en) * 2014-08-01 2018-04-18 Isto Technologies Inc. Cartilage compositions and methods for modifying proteoglycan content
EP3200838B1 (en) 2014-09-30 2019-09-18 Allergan Industrie, SAS Stable hydrogel compositions including additives
US10077420B2 (en) 2014-12-02 2018-09-18 Histogenics Corporation Cell and tissue culture container
WO2016130573A2 (en) 2015-02-09 2016-08-18 Mosaic Biosciences, Inc. Degradable thiol-ene polymers and methods of making thereof
CA2986702C (en) 2015-05-21 2023-04-04 David Wang Modified demineralized cortical bone fibers
US20180085490A1 (en) * 2015-05-29 2018-03-29 Launchpad Medical, Llc Compositions and methods for adhesion to surfaces
FR3038838B1 (fr) 2015-07-13 2017-08-18 Synolyne Pharma Chitosane pour melange avec un fluide coagulable
EP3322434A4 (en) 2015-07-14 2019-01-09 Silk Therapeutics Inc. SILK FUNCTIONAL CLOTHING AND PRODUCTS AND METHOD OF MANUFACTURING THEM
KR20170025011A (ko) * 2015-08-27 2017-03-08 고려대학교 산학협력단 통증완화약물의 지속성 방출을 위한 약학적 조성물 및 그 투여를 위한 투여 장치
US10299916B2 (en) * 2016-01-07 2019-05-28 Medtronic Vascular, Inc. Bioprosthetic tissue repair and reinforcement
US10322206B2 (en) 2016-03-29 2019-06-18 Worcester Polytechnic Institute Compositions and methods for wound healing
US9861410B2 (en) 2016-05-06 2018-01-09 Medos International Sarl Methods, devices, and systems for blood flow
CN105944149A (zh) * 2016-06-13 2016-09-21 齐鲁工业大学 一种可吸收软骨修复系统及其制备方法
CN109310800B (zh) * 2016-07-29 2022-01-07 医药研究有限公司 包含核酸和壳聚糖的肩袖撕裂修复用组合物
CN106841258A (zh) * 2016-12-30 2017-06-13 遵义医学院附属医院 一种筛选用于促进骨愈合的药物的方法
RU2651768C1 (ru) * 2017-03-07 2018-04-23 Федеральное государственное автономное образовательное учреждение высшего образования "Крымский федеральный университет имени В.И. Вернадского" (ФГАОУ ВО "КФУ им. В.И. Вернадского") Способ лечения периодонтита
CN108478864B (zh) * 2017-08-07 2020-10-23 上海交通大学医学院附属第九人民医院 复合纤维支架
CN111712514A (zh) 2017-09-27 2020-09-25 自然进化公司 丝涂布织物和产品及其制备方法
CN107753138A (zh) * 2017-11-09 2018-03-06 中山大学附属口腔医院 一种评估微量元素成骨作用的方法及其动物模型的构建方法
CN108042544B (zh) * 2017-11-21 2020-02-21 北京德得创业科技有限公司 一种甲苯胺蓝光动力杀菌及促进愈合组合物及其应用
CN107754002A (zh) * 2017-12-04 2018-03-06 广州市天河诺亚生物工程有限公司 一种具有干细胞活性的生物材料制备方法
CN108888385B (zh) * 2018-05-10 2020-08-07 北京工业大学 基于皮肤软组织形变的修复体再修复方法
JP7370560B2 (ja) * 2018-05-29 2023-10-30 公立大学法人大阪 生体活性セメントペーストおよび生体活性セメントを製造するためのキット、生体活性セメントペーストおよびその製造方法
AU2019287447A1 (en) * 2018-06-11 2021-01-14 Ocugen, Inc. Scaffold with adhesive for articular cartilage repair
ES2690392B2 (es) * 2018-07-19 2019-07-05 Univ Valencia Politecnica Material inyectable para la regeneracion del cartilago articular
JP2022502482A (ja) * 2018-09-17 2022-01-11 ボード オブ リージェンツ ザ ユニヴァーシティ オブ テキサス システム 骨損傷を治療するための組成物及び方法
US11701232B2 (en) 2019-01-15 2023-07-18 University Of Maryland, College Park Acellular bioactive scaffold device and methods of fabrication and treatment relating thereto
CN111012946B (zh) * 2019-12-31 2022-05-17 广州润虹医药科技股份有限公司 一种温敏性磷酸钙骨水泥及其制备方法
BR102020017697A2 (pt) * 2020-08-31 2022-03-15 Fundação Universidade Federal De São Carlos Processo de preparação de enxertos ósseos e enxertos ósseos obtidos
RU2765601C1 (ru) * 2021-08-17 2022-02-01 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр глазных болезней имени Гельмгольца" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ ГБ им. Гельмгольца" Минздрава России) Способ дифференцированного лечения эрозий и язв роговицы
IT202200004574A1 (it) 2022-03-10 2023-09-10 Sergio Ammendola Nanoparticelle di N-acetilglucosammina e loro applicazioni
IL300830B1 (en) * 2023-02-21 2024-04-01 Reddress Ltd A device intended for implantation that is coated with clotted blood

Family Cites Families (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2976574A (en) 1956-07-31 1961-03-28 Union Carbide Corp Chemical process and product
US3266906A (en) 1962-12-13 1966-08-16 Kelco Co Algin gel and gelatin composition having high bloom strength and process
US3586654A (en) 1969-04-15 1971-06-22 Nat Distillers Chem Corp Process for the preparation of polymer powders of controlled particle shape,size and size distribution and product
US3755558A (en) 1971-02-23 1973-08-28 Du Pont Polylactide drug mixtures for topical application atelet aggregation
IT1021282B (it) 1973-10-11 1978-01-30 Basf Ag Processo per la preparazione di dispersioni di poliesterimidi
JPS51136033A (en) * 1975-05-19 1976-11-25 Nissan Motor Co Ltd Exhaust reflux device of engine
US4060081A (en) 1975-07-15 1977-11-29 Massachusetts Institute Of Technology Multilayer membrane useful as synthetic skin
US4185618A (en) 1976-01-05 1980-01-29 Population Research, Inc. Promotion of fibrous tissue growth in fallopian tubes for female sterilization
US4195175A (en) 1978-01-03 1980-03-25 Johnson Edwin L Process for the manufacture of chitosan
US4337760A (en) 1978-10-13 1982-07-06 Adolf Schwimmer Method for the treatment of tumors with β-glucuronidase activity dependent pharmaceuticals
JPS5943041B2 (ja) 1979-02-16 1984-10-19 大日精化工業株式会社 尿素基を有する糖誘導体およびその製造方法
US4391909A (en) 1979-03-28 1983-07-05 Damon Corporation Microcapsules containing viable tissue cells
US4933105A (en) 1980-06-13 1990-06-12 Sandoz Pharm. Corp. Process for preparation of microspheres
DE3026762C2 (de) 1980-07-15 1985-04-25 Akzo Gmbh, 5600 Wuppertal Verfahren zum Herstellen von porösem, pulverförmigem Polypropylen und Verwendung der Verfahrensprodukte
US4532134A (en) * 1981-04-06 1985-07-30 Malette William Graham Method of achieving hemostasis, inhibiting fibroplasia, and promoting tissue regeneration in a tissue wound
US4394373A (en) * 1981-04-06 1983-07-19 Malette William Graham Method of achieving hemostasis
US4424346A (en) 1981-06-04 1984-01-03 Canadian Patents And Development Ltd. Derivatives of chitins, chitosans and other polysaccharides
SE441009B (sv) 1982-03-08 1985-09-02 Kjell Nilsson Sett att immobilisera levande biomaterial i perlformiga polymerer
US4605623A (en) 1982-11-08 1986-08-12 Malette William Graham Method of altering growth and development and suppressing contamination microorganisms in cell or tissue culture
US4474769A (en) 1983-05-13 1984-10-02 Pfanstiehl Laboratories, Inc. Chitosan as a contraceptive
US4568559A (en) 1984-02-06 1986-02-04 Biotek, Inc. Composite core coated microparticles and process of preparing same
US4659700A (en) 1984-03-02 1987-04-21 Johnson & Johnson Products, Inc. Chitosan-glycerol-water gel
US4722948A (en) 1984-03-16 1988-02-02 Dynatech Corporation Bone replacement and repair putty material from unsaturated polyester resin and vinyl pyrrolidone
US4731081A (en) 1984-09-11 1988-03-15 Mentor Corporation Rupture-resistant prosthesis with creasable shell and method of forming same
US4902792A (en) 1985-04-19 1990-02-20 Kanebo Ltd. Fine cellulose particles and process for production thereof
US4678470A (en) 1985-05-29 1987-07-07 American Hospital Supply Corporation Bone-grafting material
US4895724A (en) * 1985-06-07 1990-01-23 Pfizer Inc. Chitosan compositions for controlled and prolonged release of macromolecules
JPS624702A (ja) 1985-06-28 1987-01-10 Lion Corp 水溶性アシル化キトサンの製造方法
US6005161A (en) * 1986-01-28 1999-12-21 Thm Biomedical, Inc. Method and device for reconstruction of articular cartilage
US5902741A (en) * 1986-04-18 1999-05-11 Advanced Tissue Sciences, Inc. Three-dimensional cartilage cultures
US4877775A (en) 1986-06-16 1989-10-31 E. I. Du Pont De Nemours And Company Polymeric aminosaccharides as antihypercholesterolemic agents
US4803075A (en) 1986-06-25 1989-02-07 Collagen Corporation Injectable implant composition having improved intrudability
US5736372A (en) * 1986-11-20 1998-04-07 Massachusetts Institute Of Technology Biodegradable synthetic polymeric fibrous matrix containing chondrocyte for in vivo production of a cartilaginous structure
CA1340581C (en) * 1986-11-20 1999-06-08 Joseph P. Vacanti Chimeric neomorphogenesis of organs by controlled cellular implantation using artificial matrices
JPH01104305A (ja) 1987-10-15 1989-04-21 Tadashi Uragami 液体分離用膜
US4861627A (en) 1987-05-01 1989-08-29 Massachusetts Institute Of Technology Preparation of multiwall polymeric microcapsules
EP0436499B1 (en) 1987-07-10 1996-10-09 Asahi Kogaku Kogyo Kabushiki Kaisha A process for producing a calcium phosphate type powder
US5306311A (en) * 1987-07-20 1994-04-26 Regen Corporation Prosthetic articular cartilage
US6610669B1 (en) * 1987-09-18 2003-08-26 Genzyme Corporation Water insoluble derivatives of polyanionic polysaccharides
GB8803697D0 (en) * 1988-02-17 1988-03-16 Deltanine Research Ltd Clinical developments using amniotic membrane cells
US4956350A (en) * 1988-08-18 1990-09-11 Minnesota Mining And Manufacturing Company Wound filling compositions
US5843156A (en) 1988-08-24 1998-12-01 Endoluminal Therapeutics, Inc. Local polymeric gel cellular therapy
US4938763B1 (en) * 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
US5126141A (en) 1988-11-16 1992-06-30 Mediventures Incorporated Composition and method for post-surgical adhesion reduction with thermo-irreversible gels of polyoxyalkylene polymers and ionic polysaccharides
US5073202A (en) 1989-03-09 1991-12-17 Micro Vesicular Systems, Inc. Method of using a biodegradable superabsorbing sponge
US5324519A (en) * 1989-07-24 1994-06-28 Atrix Laboratories, Inc. Biodegradable polymer composition
WO1991001720A1 (en) 1989-08-07 1991-02-21 Herman Wade Schlameus Composition and method of promoting hard tissue healing
JPH0678372B2 (ja) 1990-06-19 1994-10-05 信越化学工業株式会社 重合体スケール付着防止用溶液および重合体スケールの付着防止方法
US5071644A (en) 1990-08-07 1991-12-10 Mediventures, Inc. Topical drug delivery with thermo-irreversible gels
US5811094A (en) * 1990-11-16 1998-09-22 Osiris Therapeutics, Inc. Connective tissue regeneration using human mesenchymal stem cell preparations
US5047055A (en) 1990-12-21 1991-09-10 Pfizer Hospital Products Group, Inc. Hydrogel intervertebral disc nucleus
US5318780A (en) 1991-10-30 1994-06-07 Mediventures Inc. Medical uses of in situ formed gels
GB2261672A (en) * 1991-11-18 1993-05-26 Michael Braden The use of biomaterials for tissue repair
IL100096A (en) 1991-11-20 1996-03-31 Univ Ramot Method for entrapment of active materials in chitosan
US5658593A (en) 1992-01-16 1997-08-19 Coletica Injectable compositions containing collagen microcapsules
US5708152A (en) 1992-03-27 1998-01-13 Ciba Specialty Chemicals Corporation N-substituted chitosan derivatives in a process for their preparation
US5266326A (en) 1992-06-30 1993-11-30 Pfizer Hospital Products Group, Inc. In situ modification of alginate
US5871985A (en) * 1992-09-28 1999-02-16 Brown University Research Foundation Particulate non cross-linked chitosan core matrices for encapsulated cells
US5318710A (en) * 1993-03-12 1994-06-07 Chevron Research And Technology Company Low viscosity Group II metal overbased sulfurized C16 to C22 alkylphenate compositions
US5709854A (en) * 1993-04-30 1998-01-20 Massachusetts Institute Of Technology Tissue formation by injecting a cell-polymeric solution that gels in vivo
US5368051A (en) * 1993-06-30 1994-11-29 Dunn; Allan R. Method of regenerating articular cartilage
CA2130295A1 (en) 1993-08-26 1995-02-27 Richard A. Berg Ionically crosslinked glycosaminoglycan gels for soft tissue augmentation and drug delivery
US5531716A (en) * 1993-09-29 1996-07-02 Hercules Incorporated Medical devices subject to triggered disintegration
US6743783B1 (en) * 1993-12-01 2004-06-01 Marine Polymer Technologies, Inc. Pharmaceutical compositions comprising poly-β-1→4-N-acetylglucosamine
US5422116A (en) 1994-02-18 1995-06-06 Ciba-Geigy Corporation Liquid ophthalmic sustained release delivery system
US5626861A (en) 1994-04-01 1997-05-06 Massachusetts Institute Of Technology Polymeric-hydroxyapatite bone composite
US5723331A (en) * 1994-05-05 1998-03-03 Genzyme Corporation Methods and compositions for the repair of articular cartilage defects in mammals
DK0952792T3 (da) * 1994-06-06 2003-12-08 Osiris Therapeutics Inc Biomatrix til vævsregeneration
US5837235A (en) * 1994-07-08 1998-11-17 Sulzer Medizinaltechnik Ag Process for regenerating bone and cartilage
SE9402531L (sv) * 1994-07-19 1996-01-20 Medicarb Ab Sårläkningsmedel
SE9402528D0 (sv) * 1994-07-19 1994-07-19 Astra Ab Hårdvävnadsstimulerande med el
US5510102A (en) * 1995-01-23 1996-04-23 The Regents Of The University Of California Plasma and polymer containing surgical hemostatic adhesives
US5749874A (en) * 1995-02-07 1998-05-12 Matrix Biotechnologies, Inc. Cartilage repair unit and method of assembling same
US6080194A (en) * 1995-02-10 2000-06-27 The Hospital For Joint Disease Orthopaedic Institute Multi-stage collagen-based template or implant for use in the repair of cartilage lesions
US5906934A (en) * 1995-03-14 1999-05-25 Morphogen Pharmaceuticals, Inc. Mesenchymal stem cells for cartilage repair
US5620706A (en) * 1995-04-10 1997-04-15 Universite De Sherbrooke Polyionic insoluble hydrogels comprising xanthan and chitosan
US5655546A (en) * 1995-06-07 1997-08-12 Halpern; Alan A. Method for cartilage repair
WO1996041818A1 (en) * 1995-06-09 1996-12-27 Drohan William N Chitin hydrogels, methods of their production and use
JP3881707B2 (ja) 1995-07-20 2007-02-14 学校法人松本歯科大学 骨形成促進剤の製造方法及び骨形成促進剤を用いた骨形成組成物の製造方法
US5900238A (en) 1995-07-27 1999-05-04 Immunex Corporation Vaccine delivery system
TW389694B (en) 1995-08-17 2000-05-11 Novartis Ag Compositions including o-carboxyalkyl chitosan and methods of use in ophthalmics
ATE258810T1 (de) 1995-11-09 2004-02-15 Univ Massachusetts Wiederherstellung der gewebeoberfläche mit zusammensetzungen aus hydrogel-zellen
US5908784A (en) * 1995-11-16 1999-06-01 Case Western Reserve University In vitro chondrogenic induction of human mesenchymal stem cells
JPH09143093A (ja) * 1995-11-17 1997-06-03 Hoechst Japan Ltd 軟骨・骨誘導性修復用材料
DK2111876T3 (da) 1995-12-18 2011-12-12 Angiodevice Internat Gmbh Tværbundne polymerpræparater og fremgangsmåder til anvendelse deraf
US6200606B1 (en) * 1996-01-16 2001-03-13 Depuy Orthopaedics, Inc. Isolation of precursor cells from hematopoietic and nonhematopoietic tissues and their use in vivo bone and cartilage regeneration
US5842477A (en) * 1996-02-21 1998-12-01 Advanced Tissue Sciences, Inc. Method for repairing cartilage
IL118376A0 (en) * 1996-05-22 1996-09-12 Univ Ben Gurion Polysaccharide sponges for cell culture and transplantation
US5830503A (en) 1996-06-21 1998-11-03 Andrx Pharmaceuticals, Inc. Enteric coated diltiazem once-a-day formulation
US6060534A (en) 1996-07-11 2000-05-09 Scimed Life Systems, Inc. Medical devices comprising ionically and non-ionically crosslinked polymer hydrogels having improved mechanical properties
US6649192B2 (en) * 1996-07-29 2003-11-18 Universidade De Santiago De Compostela Application of nanoparticles based on hydrophilic polymers as pharmaceutical forms
US5964807A (en) 1996-08-08 1999-10-12 Trustees Of The University Of Pennsylvania Compositions and methods for intervertebral disc reformation
US5872880A (en) * 1996-08-12 1999-02-16 Ronald S. Maynard Hybrid-optical multi-axis beam steering apparatus
US7320962B2 (en) 1996-08-27 2008-01-22 Baxter International Inc. Hemoactive compositions and methods for their manufacture and use
US6706690B2 (en) 1999-06-10 2004-03-16 Baxter Healthcare Corporation Hemoactive compositions and methods for their manufacture and use
WO1998022114A1 (en) 1996-11-15 1998-05-28 Dumex-Alpharma A/S A method for promoting tissue repair
JPH10259134A (ja) * 1997-01-16 1998-09-29 Sekisui Chem Co Ltd 創傷治癒促進剤
US5866415A (en) * 1997-03-25 1999-02-02 Villeneuve; Peter E. Materials for healing cartilage and bone defects
US5981221A (en) * 1997-03-26 1999-11-09 Incyte Pharmaceuticals, Inc. Histone fusion protein
CA2212300A1 (en) * 1997-08-04 1999-02-04 Abdellatif Chenite In vitro or in vivo gelfying chitosan and therapeutic uses thereof
US6110209A (en) * 1997-08-07 2000-08-29 Stone; Kevin R. Method and paste for articular cartilage transplantation
US6417247B1 (en) 1997-10-14 2002-07-09 Beth L. Armstrong Polymer/ceramic composites
CA2219399A1 (en) * 1997-10-24 1999-04-24 Bio Syntech Ltd. Bulk formation of monolithic polysaccharide-based hydrogels
JP2001521786A (ja) * 1997-10-30 2001-11-13 ザ ジュネラル ホスピタル コーポレーション 単離軟骨細胞を使用した軟骨性基質の接着
US7019192B2 (en) 1998-02-27 2006-03-28 Musculoskeletal Transplant Foundation Composition for filling bone defects
US6911212B2 (en) * 1998-02-27 2005-06-28 Musculoskeletal Transplant Foundation Malleable putty and flowable paste with allograft bone having residual calcium for filling bone defects
US7045141B2 (en) * 1998-02-27 2006-05-16 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
EP1056413A4 (en) 1998-02-27 2003-08-20 Bioelastics Res Ltd INJECTABLE IMPLANTS FOR TISSUE ENHANCEMENT AND RESTORATION
US6179872B1 (en) * 1998-03-17 2001-01-30 Tissue Engineering Biopolymer matt for use in tissue repair and reconstruction
AU3097999A (en) * 1998-03-18 1999-10-11 University Of Pittsburgh Chitosan-based composite materials containing glycosaminoglycan for cartilage repair
US20030147860A1 (en) 2002-02-07 2003-08-07 Marchosky J. Alexander Compositions and methods for forming and strengthening bone
DE19817698A1 (de) 1998-04-22 1999-10-28 Jan Zoellner Verwendung einer autopolymerisierenden Zusammensetzung auf Organosiloxanbasis
US6060514A (en) * 1998-05-04 2000-05-09 Conlin Co., Inc. Isomer enriched conjugated linoleic acid compositions
AU756785B2 (en) 1998-07-13 2003-01-23 University Of Southern California Methods for accelerating bone and cartilage growth and repair
JP2002535378A (ja) 1999-02-01 2002-10-22 ジェネティックス・インスチチュート・インコーポレーテッド 関節軟骨の治癒および修復のための方法および組成物
JP2002537022A (ja) 1999-02-16 2002-11-05 ズルツァー バイオロジクス インコーポレイテッド 軟骨病変を再生して修復する装置及び方法
US6436143B1 (en) 1999-02-22 2002-08-20 Anthony C. Ross Method and apparatus for treating intervertebral disks
US6294187B1 (en) * 1999-02-23 2001-09-25 Osteotech, Inc. Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same
AU5311700A (en) * 1999-06-01 2000-12-28 Closys Corporation Clotting cascade initiating apparatus and methods of use
WO2001000792A1 (en) 1999-06-29 2001-01-04 Marchosky J Alexander Compositions and methods for forming and strengthening bone
US6429013B1 (en) 1999-08-19 2002-08-06 Artecel Science, Inc. Use of adipose tissue-derived stromal cells for chondrocyte differentiation and cartilage repair
EP1229940B1 (en) * 1999-11-15 2014-05-14 Piramal Healthcare (Canada) Limited Temperature-controlled and ph-dependant self-gelling biopolymeric aqueous solution
US20030158302A1 (en) * 1999-12-09 2003-08-21 Cyric Chaput Mineral-polymer hybrid composition
AU1979201A (en) * 1999-12-09 2001-06-18 Bio Syntech Canada Inc Mineral-polymer hybrid composition
US20050244393A1 (en) 1999-12-22 2005-11-03 Henogen S.A. Sealant or tissue generating product
WO2001048148A1 (en) * 1999-12-28 2001-07-05 The Regents Of The University Of Michigan Process for ex vivo formation of mammalian bone and uses thereof
DE10026467A1 (de) * 2000-05-27 2001-12-13 Prec Motors Deutsche Minebea G Spindelmotor für Festplattenlaufwerke mit verbesserter Laufgenauigkeit
US20020082220A1 (en) 2000-06-29 2002-06-27 Hoemann Caroline D. Composition and method for the repair and regeneration of cartilage and other tissues
US6866866B1 (en) 2000-11-03 2005-03-15 Andrx Labs, Llc Controlled release metformin compositions
US20040047892A1 (en) 2000-11-15 2004-03-11 Desrosiers Eric Andre Filler composition for soft tissue augmentation and reconstructive surgery
EP1335687B1 (en) * 2000-11-15 2007-01-10 Bio Syntech Canada Inc. Method for restoring a damaged or degenerated intervertebral disc
US6756363B1 (en) 2000-11-17 2004-06-29 Wound Healing Of Oklahoma, Inc. Solutions and films of glycated chitosan
US20020146385A1 (en) * 2001-04-10 2002-10-10 Lin Tung Liang Ionic antimicrobial coating
JP2002344242A (ja) * 2001-05-18 2002-11-29 Nippon Precision Circuits Inc 電圧制御発振器
EP1416944B1 (en) * 2001-08-14 2005-12-14 Medipost, Co., Ltd. Composition for treatment of articular cartilage damage
US8740973B2 (en) * 2001-10-26 2014-06-03 Icon Medical Corp. Polymer biodegradable medical device
TW200408407A (en) * 2001-11-30 2004-06-01 Dana Farber Cancer Inst Inc Methods and compositions for modulating the immune system and uses thereof
DK1455802T3 (da) * 2001-12-14 2009-02-16 Dnp Canada Inc Anvendelser af chitosanoligosaccharider
TWI245634B (en) 2001-12-28 2005-12-21 Ind Tech Res Inst Preparation of a biodegradable thermal-sensitive gel system
JP3933949B2 (ja) * 2002-02-05 2007-06-20 三菱電機株式会社 反射鏡支持機構
US7514249B2 (en) * 2002-04-18 2009-04-07 The University Of Florida Research Foundation, Inc. Biomimetic organic/inorganic composites
US20060204544A1 (en) * 2002-05-20 2006-09-14 Musculoskeletal Transplant Foundation Allograft bone composition having a gelatin binder
ES2321505T3 (es) 2002-07-31 2009-06-08 Alza Corporation Composiciones de deposito de polimero multimodal inyectables y empleo de las mismas.
MXPA05001242A (es) 2002-07-31 2005-06-08 Alza Corp Composiciones de deposito inyectable y usos de las mismas.
EP1389667B1 (de) * 2002-08-14 2007-01-17 Herrenknecht AG Schildschwanz für eine Schildvortriebseinrichtung
CA2500220A1 (en) * 2002-09-30 2004-04-08 Regen Biotech, Inc. Composition for stimulating bone-formation and bone consolidation
RU2355385C2 (ru) * 2002-11-06 2009-05-20 Алза Корпорейшн Композиции пролонгированного действия с контролируемым высвобождением
GB0302738D0 (en) * 2003-02-06 2003-03-12 Advanced Biopolymers As Composition
US7217294B2 (en) * 2003-08-20 2007-05-15 Histogenics Corp. Acellular matrix implants for treatment of articular cartilage, bone or osteochondral defects and injuries and method for use thereof
GB0403938D0 (en) * 2004-02-21 2004-03-24 West Pharm Serv Drug Res Ltd Chitosan containing solution
US20060062768A1 (en) * 2004-09-23 2006-03-23 Olexander Hnojewyj Biocompatible hydrogel compositions
ITRM20040539A1 (it) * 2004-11-02 2005-02-02 Mavi Sud S R L Preparati a base di chitina o suoi derivati per uso cosmetico o medico.
US7309622B2 (en) * 2005-02-14 2007-12-18 Stats Chippac Ltd. Integrated circuit package system with heat sink
US20070254007A1 (en) * 2006-04-25 2007-11-01 Bumgardner Joel D Chitosan/nanocrystalline hydroxyapatite composite microsphere-based scaffolds
CA2672936A1 (en) 2006-11-30 2008-06-05 Bio Syntech Canada Inc. Method for in situ solidification of blood-polymer compositions for regenerative medicine and cartilage repair applications
US8153612B2 (en) * 2006-12-11 2012-04-10 Chi2Gel Ltd. Injectable chitosan mixtures forming hydrogels
US7776840B2 (en) * 2007-02-21 2010-08-17 Cutanea Life Sciences, Inc. Methods of use of biomaterial and injectable implant containing biomaterial

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10179145B2 (en) 2007-03-16 2019-01-15 University Of Maryland, College Park Advanced functional biocompatible polymeric matrix used as a hemostatic agent and system for damaged tissues and cells

Also Published As

Publication number Publication date
AU6888201A (en) 2002-01-08
WO2002000272A2 (en) 2002-01-03
US20070037737A1 (en) 2007-02-15
JP2004501682A (ja) 2004-01-22
CN1471412A (zh) 2004-01-28
CA2412505A1 (en) 2002-01-03
EP1294414A2 (en) 2003-03-26
CY1106313T1 (el) 2011-10-12
DE60117984T2 (de) 2006-12-14
WO2002000272A3 (en) 2002-08-08
CN1471412B8 (zh) 2016-06-15
KR100880622B1 (ko) 2009-01-30
US20110086008A1 (en) 2011-04-14
JP5089006B2 (ja) 2012-12-05
HK1055563A1 (en) 2004-01-16
DE60117984T8 (de) 2007-06-14
CN1471412B (zh) 2010-10-20
CA2412505C (en) 2009-02-03
US20020082220A1 (en) 2002-06-27
PT1294414E (pt) 2006-07-31
MXPA03000203A (es) 2004-09-13
ZA200300597B (en) 2004-02-19
SG149679A1 (en) 2009-02-27
ES2260241T3 (es) 2006-11-01
IL153490A (en) 2007-12-03
DK1294414T3 (da) 2006-07-24
NZ523763A (en) 2005-02-25
DE60117984D1 (de) 2006-05-11
US7148209B2 (en) 2006-12-12
KR20030027904A (ko) 2003-04-07
US20060029578A1 (en) 2006-02-09
BR0112109A (pt) 2007-05-29
IL153490A0 (en) 2003-07-06
US8258117B2 (en) 2012-09-04
AU2001268882B2 (en) 2006-07-06
ATE320277T1 (de) 2006-04-15

Similar Documents

Publication Publication Date Title
EP1294414B1 (en) Composition and method for the repair and regeneration of cartilage and other tissues
AU2001268882A1 (en) Composition and method for the repair and regeneration of cartilage and other tissues
EP3189859B1 (en) Composition for treatment of cartilage disease
US9827293B2 (en) Non-surgical, localized delivery of compositions for placental growth factors
US11690896B2 (en) Non-surgical, localized delivery of compositions for placental growth factors
EP2210621B1 (en) Composition for the treatment of rheumatoid arthritis
Class et al. Patent application title: COMPOSITION AND METHOD FOR THE REPAIR AND REGENERATION OF CARTILAGE AND OTHER TISSUES Inventors: Caroline D. Hoemann (Montreal, CA) Michael D. Buschmann (Montreal, CA) Michael D. Buschmann (Montreal, CA) Marc D. Mckee (Westmount, CA)
WO2011060554A1 (en) Presolidified composition and method for in situ delivery of broad molecular weight range of chitosan implants with or without therapeutics for regenerative medicine and cartilage repair applications
AU2016318155B2 (en) Non-surgical, localized delivery of compositions for placental growth factors
Arslan et al. Therapeutic nanomaterials for cartilage regeneration
AU2013204006B2 (en) Composition for treatment of cartilage disease
Labusca et al. Recent Patents in Cartilage Regeneration

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030115

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20030521

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60117984

Country of ref document: DE

Date of ref document: 20060511

Kind code of ref document: P

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1055563

Country of ref document: HK

RIN2 Information on inventor provided after grant (corrected)

Inventor name: BUSCHMANN, MICHAEL, D.

Inventor name: MCKEE, MARC, D.

Inventor name: HOEMANN, CAROLINE, D.

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: BRAUNPAT BRAUN EDER AG

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Effective date: 20060530

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20060401992

Country of ref document: GR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2260241

Country of ref document: ES

Kind code of ref document: T3

ET Fr: translation filed
RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: BIO SYNTECH CANADA INC.

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

NLT2 Nl: modifications (of names), taken from the european patent patent bulletin

Owner name: BIO SYNTECH CANADA INC.

Effective date: 20061206

26N No opposition filed

Effective date: 20061218

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: BIO SYNTECH CANADA INC.

Free format text: BIOSYNTECH CANADA INC.#475 ARMAND FRAPPIER BOULEVARD#LAVAL, QUEBEC H7V 4B3 (CA) -TRANSFER TO- BIO SYNTECH CANADA INC.#475 ARMAND-FRAPPIER BLVD. LAVAL,#QUEBEC H7V 4B3 (CA)

NLT1 Nl: modifications of names registered in virtue of documents presented to the patent office pursuant to art. 16 a, paragraph 1

Owner name: BIO SYNTECH CANADA INC.

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20110113 AND 20110119

REG Reference to a national code

Ref country code: PT

Ref legal event code: PC4A

Owner name: PIRAMAL HEALTHCARE (CANADA) LIMITED, CA

Effective date: 20110216

REG Reference to a national code

Ref country code: CH

Ref legal event code: PUE

Owner name: PIRAMAL HEALTHCARE (CANADA) LIMITED

Free format text: BIO SYNTECH CANADA INC.#475 ARMAND-FRAPPIER BLVD. LAVAL,#QUEBEC H7V 4B3 (CA) -TRANSFER TO- PIRAMAL HEALTHCARE (CANADA) LIMITED#110 INDUSTRIAL PARKWAY NORTH#AURORA, ON L4G 3H4 (CA)

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

Owner name: PIRAMAL HEALTHCARE (CANADA) LIMITED, CA

Effective date: 20120127

REG Reference to a national code

Ref country code: AT

Ref legal event code: PC

Ref document number: 320277

Country of ref document: AT

Kind code of ref document: T

Owner name: PIRAMAL HEALTHCARE (CANADA) LIMITED, CA

Effective date: 20120124

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: PIRAMAL HEALTHCARE (CANADA) LIMITED

Effective date: 20120507

REG Reference to a national code

Ref country code: NL

Ref legal event code: SD

Effective date: 20120607

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: VON KREISLER SELTING WERNER, DE

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: VON KREISLER SELTING WERNER - PARTNERSCHAFT VO, DE

Effective date: 20120703

Ref country code: DE

Ref legal event code: R081

Ref document number: 60117984

Country of ref document: DE

Owner name: PIRAMAL HEALTHCARE (CANADA) LTD., CA

Free format text: FORMER OWNER: BIO SYNTECH CANADA INC., LAVAL, QUEBEC, CA

Effective date: 20120703

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: DOMPATENT VON KREISLER SELTING WERNER - PARTNE, DE

Effective date: 20120703

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: MURGITROYD & COMPANY, DE

Effective date: 20120703

Ref country code: DE

Ref legal event code: R081

Ref document number: 60117984

Country of ref document: DE

Owner name: SMITH & NEPHEW ORTHOPAEDICS AG, CH

Free format text: FORMER OWNER: BIO SYNTECH CANADA INC., LAVAL, QUEBEC, CA

Effective date: 20120703

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20140630

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160112

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: MURGITROYD & COMPANY, DE

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20060401992

Country of ref document: GR

Effective date: 20160112

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: MURGITROYD AND COMPANY, CH

Ref country code: CH

Ref legal event code: PUE

Owner name: SMITH AND NEPHEW ORTHOPAEDICS AG, CH

Free format text: FORMER OWNER: PIRAMAL HEALTHCARE (CANADA) LIMITED, CA

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20160728 AND 20160803

REG Reference to a national code

Ref country code: FR

Ref legal event code: TP

Owner name: SMITH & NEPHEW ORTHOPEADICS AG, CH

Effective date: 20160718

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: MURGITROYD & COMPANY, DE

Ref country code: DE

Ref legal event code: R081

Ref document number: 60117984

Country of ref document: DE

Owner name: SMITH & NEPHEW ORTHOPAEDICS AG, CH

Free format text: FORMER OWNER: PIRAMAL HEALTHCARE (CANADA) LTD., AURORA, CA

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20170428

Year of fee payment: 17

Ref country code: FR

Payment date: 20170511

Year of fee payment: 17

Ref country code: IE

Payment date: 20170609

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20170626

Year of fee payment: 17

Ref country code: SE

Payment date: 20170613

Year of fee payment: 17

Ref country code: BE

Payment date: 20170424

Year of fee payment: 17

Ref country code: LU

Payment date: 20170608

Year of fee payment: 17

Ref country code: NL

Payment date: 20170614

Year of fee payment: 17

Ref country code: AT

Payment date: 20170525

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20170601

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20171101

Year of fee payment: 17

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20180630

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20181231

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180630

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180629

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180629

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20180701

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 320277

Country of ref document: AT

Kind code of ref document: T

Effective date: 20180629

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20180630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180629

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180702

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180701

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180629

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180630

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180630

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20190618

Year of fee payment: 19

Ref country code: IT

Payment date: 20190620

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20190614

Year of fee payment: 19

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20190701

Year of fee payment: 19

Ref country code: GB

Payment date: 20190626

Year of fee payment: 19

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 60117984

Country of ref document: DE

Representative=s name: MURGITROYD & COMPANY, DE

Ref country code: DE

Ref legal event code: R081

Ref document number: 60117984

Country of ref document: DE

Owner name: SMITH & NEPHEW ORTHOPAEDICS AG, CH

Free format text: FORMER OWNER: SMITH & NEPHEW ORTHOPAEDICS AG, BAAR, CH

REG Reference to a national code

Ref country code: CH

Ref legal event code: PCOW

Free format text: NEW ADDRESS: THEILERSTRASSE 1A, 6300 ZUG (CH)

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 60117984

Country of ref document: DE

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20200629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200629

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210101

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20211103

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190629